This thread contains multiple links/information. This information is not confirmed/checked by Fertility Friends and readers are reminded that FertilityFriends.co.uk or its owners are not responsible for the content or accuracy of external internet sites, or of the accuracy of medical information shared by members other than those in our "Ask A Professional" section. Please also read the author's notes at the bottom of this post.

**For a more print friendly version of this whole thread, Click here** (but don't expect it to be the same tomorrow - more info is trickling in every few days!)

To go directly to each section, click on the large blue letter in the index.

3.2 Bleeding in pregnancy3.2.1 I am spotting/bleeding in pregnancy – am I miscarrying?3.2.2 I am spotting/bleeding in pregnancy – what should I do?3.2.3 Will bed rest help the pregnancy if I am bleeding/spotting?

3.3 Breastfeeding3.3.1 Why should I breastfeed my immune Tx baby?3.3.2 Can all babies breastfeed? Can all mothers make enough milk to breastfeed?

4.2 Chlamydia Trachomatis4.2.1 What is Chlamydia?4.2.2 How is Chlamydia tested?4.2.3 How could I test positive for Chlamydia when I have tested negative on other tests?4.2.4 How could I test positive for Chlamydia when I have previously had antibiotics for it?4.2.5 Why should I have the Chlamydia test?4.2.6 What do I need to know about the Chlamydia test by menstrual blood PCR?4.2.7 How much does the Greek Chlamydia test cost?4.2.8 How long will the results take to come back?4.2.9 What is the treatment for Chlamydia?4.2.10 When should I retest for Chlamydia after treatment?4.2.11 Do I have to clear Chlamydia before I can cycle?4.2.12 My partner doesn't want to take all these long courses of antibiotics. Does he have to?

4.3 Clexane (lovenox), fragmin, aspirin and other blood thinners4.3.1 What are heparins? What are they used for in fertility treatment?4.3.2 How do I take clexane?4.3.3 When do I start and stop clexane?4.3.4 What are the risks/side effects of clexane?4.3.5 How much does clexane cost?4.3.6 Where should I fill my prescription for clexane?4.3.7 Will my GP prescribe clexane for fertility or during pregnancy?4.3.8 How is aspirin taken?

for Cordyceps, see Mycology, below

4.4 Corticosteroids (‘steroids’) – prednisolone, dexamethasone, prednisone4.4.1 What are corticosteroids? What are corticosteroids used for in fertility treatment?4.4.2 How do you take corticosteroids?4.4.3 When/how do I stop taking corticosteroids?4.4.4 What are the risks/side effects of corticosteroids?4.4.5 How much do steroids cost?4.4.6 What conditions are steroids normally prescribed for?

4.5 Costs4.5.1 How much does immune testing and treatment cost? 4.5.2 Do you have any tips to save on costs?4.5.3 How do ladies find the money to pay for their Tx plus immunes?4.5.4 I cannot afford any immune testing or any of these immune treatments. Are there any other possibilities?4.5.5 I am pregnant and panicking about the costs of ongoing immunes. How much do I really need to buy for baby? Can I cut costs?

4.6 Cytokine ratio (TH1:TH2) test4.6.1 What is the cytokine ratio test? 4.6.2 Please explain my cytokine ratio test results?4.6.3 How is the cytokine ratio test different to a TNFa measurement test?4.6.4 What are the sample requirements for the cytokine ratio test at RFU Chicago?4.6.5 How long does it take to get the results of the cytokine ratio test back?4.6.6 What are the treatment options for high TNFa ratio?4.6.7 How much does the cytokine ratio test cost?

5.1 Deciding to see a reproductive immune specialist5.1.1 What are the most common reasons for deciding to have immune testing/see a reproductive immune specialist?

5.2 Diet5.2.1 Is there anything I should eat or avoid eating to help my immune issues?

5.3 DQ Alpha Genotype (DQa) test5.3.1 What is the HLA-DQa test?5.3.2 How much does the DQa test cost?5.3.3 How do I understand my DQa results?5.3.4 If I have DQa matches, what can I do?5.3.5 Why do people worry about having a (4.1, 4.1) embryo?5.3.6 Should I have the DQa test?5.3.7 How long do DQa results take to come back?5.3.8 What are the sample requirements for the DQa test at RFU ?

7.2 Fears about immune treatment7.2.1 I am worried about taking immune drugs (prednisolone, clexane, Humira, intralipids, IVIg)7.2.2 I am worried about giving myself injections7.2.3 I am worried because I am getting different advice from different doctors 7.2.4 I am worried because I forgot to take my medication on time or that I don’t understand the instructions7.2.5 I am worried that my cycle won’t work because I am stressed, or that my treatment has not gone as smoothly as I was expecting

8.1 G-CSF/neupogen and KIR testing8.1.1 What is G/CSF therapy?8.1.2 Practical aspects of G/CSF therapy 8.1.3 Should I test for the KIR activator defects8.1.4 What does my KIR result mean?

8.2 Gestone (and cyclogest, crinone, utrogestan)- progesterone8.2.1 Why is extra progesterone often prescribed for immune Tx?8.2.2 How are progesterones administered?8.2.3 Can progesterone prevent a threatened miscarriage?8.2.4 How much does gestone cost?8.2.5 Can you take too much progesterone?

9.2 Humira9.2.1 What is Humira? What is it used for in fertility treatment?9.2.2 How is Humira given?9.2.3 What the risks/side effects of Humira?9.2.4 Why do I need a TB test before Humira?9.2.5 When should I retest my cytokine ratio after Humira?9.2.6 How long does Humira last in your system? How long before my treatment should I take it?9.2.7 How much does Humira cost?9.2.8 Do I have to have Humira? Can I get/stay pregnant without it?

10.1 Insulin resistance/gestational diabetes/polycystic ovaries10.1.1 Should I be tested for insulin resistance?10.1.2 What can I do about insulin resistance/PCOS?

10.2 Intralipids10.2.1 What are intralipids? What do they do?10.2.2 How long do the benefits of intralipids last?10.2.3 Who can’t have intralipids?10.2.4 What are the risks/side effects of intralipids?10.2.5 How are intralipids given?10.2.6 Can I have intralipids administered outside of London?10.2.7 Can I have intralipids administered on a weekend?10.2.8 How much do intralipids cost?10.2.9 How often do I need intralipids?10.2.10 When do I stop intralipids?10.4.11 What supplies do you need?10.2.12 Can I work whilst the drip is given?

10.3 IVF10.3.1 Can I have IVF with my NHS clinic/local clinic/abroad but still have specialist immune treatment?10.3.2 Does it matter where I have IVF or what protocol is used?10.3.3 What is the long protocol? The Short protocol? The A/ACP? Mini-IVF? Micro flare? Estrogen priming protocol10.3.4 What is the best stimulation drug?10.3.5 How do I decide whether to have donor egg or own egg IVF?10.3.6 What strategies are used to improve IVF outcomes?10.3.7 How can I estimate my chances of IVF working for me?

10.4 IVIG10.4.1 What is IVIG? What does it do?10.4.2 How long do the benefits of IVIG last?10.4.3 Who can’t have IVIG?10.4.4 What are the risks/side effects of IVIG?10.4.5 How is IVIG given?10.4.6 Can I have IVIG administered on a weekend?10.4.7 Can I have IVIG administered outside of London?10.4.8 How much does IVIG cost?10.4.9 How often do I need IVIG?10.4.10 What supplies do you need?10.2.11 Can I work whilst the drip is given?

13.1 LAD test13.1.2 Should I have the LAD test?13.1.3 How much does the LAD test cost?13.1.4 What are the sample requirements for the LAD test at RFU Chicago?

13.2 Level 1 tests

13.3 Level 2 tests

13.4 Lining issues13.4.1 What treatments are available for a thin uterine lining?13.4.2 What is a good lining and how is poor lining diagnosed?

13.5 LIT13.5.1 What is LIT (Lymphocyte Immune Therapy)?13.5.2 Why is LIT controversial?13.5.3 What are the alternatives to LIT?13.5.4 Do I have to have LIT? Will I get pregnant/stay pregnant without it?13.5.5 Which immune doctors support LIT? Who doesn’t promote it? (see below for where you can have LIT performed)13.5.6 How do I decide whether to have paternal or donor LIT?13.5.7 What is pooled donor LIT?13.5.8 How long does LIT last?13.5.9 I still don’t understand LIT or donor LIT?13.5.10 Would I still want LIT/LAD test if I am using egg donation?13.5.11 Would I still want LIT/LAD test if I am using donor sperm?13.5.12 Can I have LIT if I am pregnant?13.5.13 Where can I get LIT?13.5.14 Do I need to worry about my Rh- status when having LIT?13.5.15 What medication can reduce the effectiveness of LIT?13.5.16 Who can be a donor for LIT?13.5.17 What screening tests does my partner (or donor) need?13.5.18 Are the test requirements strict?13.5.19 How much does LIT cost?13.5.20 How do I retest my LAD after LIT?13.5.21 How can I book in with Dr Tsagaris in Athens and ask any queries?13.5.22 Where is the LIT clinic in Athens? What’s the procedure? How long will it take?13.5.23 Is it difficult travelling to Athens and getting to the clinic?13.5.24 When should I have LIT?

15.1 Natural conception with immune treatment15.1.1 Can I try naturally with immune treatment or do I have to do IVF?

15.2 NK assay/K562 test/NK cytoxicity assay15.2.1 What is the NK assay? 15.2.2 How is the NK assay different from NK measurement/absolute NK level? How is it different from a uterine biopsy for NKs?15.2.3 What is the K562 test plus immunophenotype?15.2.4 Please explain my NK assay results?15.2.5 What is the difference between the NK assay and the NK retest (at RFU Chicago)?15.2.6 How much does the NK assay cost?15.2.7 How do I get an NK assay run with intralipids as well as with IVIG?15.2.8 What are the sample requirements for the NK assay?15.2.9 Should I have the NK assay test?15.2.10 How long do the results take to come back?15.2.11 What are the treatment options for elevated NKa?15.2.12 What alternative NK tests are there?

17.5 Pregnancy (also see two week wait and pregnancy - below)17.5.1 What immune testing and treatment protocols are typically followed in pregnancy?17.5.2 My NKa has gone up in pregnancy – is this normal? What do I do? Will it harm my pregnancy?17.5.3 My pregnancy test after immune Tx was positive - What do I need to do?17.5.4 What is NHS 'low risk' and 'high risk' pregnancy care?17.5.5 Do I need to keep having retests during pregnancy?17.5.6 What are adequate progesterone levels in early pregnancy?17.5.7 Where can I see normal embryonic/fetal growth charts? Is my scan normal?17.5.7 Where can I see normal embryonic/fetal growth charts? Is my scan normal? 17.5.8 Is my bHCG normal?17.5.9 What is my due date? How many weeks pregnant am I?17.5.10 My bHCG has risen less than 66% in 48 hours - can I do anything?

19.3 RFU Chicago and RIC (UK) 19.3.1 How do I check which tubes I need for my Chicago tests?19.3.2 Where can I find contact details for RFU Chicago?19.3.3 How do the tests on offer at RIC (UK) compare to those at RFU (Chicago)?

21.1 Tests21.1.1 Which tests do I really need?21.2 Thrombophilias – MTHFR, PAI-1, Factor V Leiden, APLAs21.2.1 What are they?21.2.2 How are they tested for?21.2.3 How are they treated?21.2.4 Where can I get more information/support?

21.3 Thyroid tests21.3.1 Do I need my thyroid activity testing?21.3.2 What is thyroid peroxidase? What is thyroglobulin antibody?21.3.3 What thyroid tests do I need?21.3.4 What causes thyroid problems?21.3.5 What are the symptoms of under or overactive thyroid?

21.4 TNFa – see cytokine ratio

21.5 Timescales for immune treatment21.5.1 What sort of timescale is typical for immune testing and treatment?

21.6 Tocolytics - atisoban, nifedipine, ritodrine - 'womb relaxants'

21.7 Treating empirically21.7.1 What is treating empirically? Can I just take immune meds without testing?

21.8 Trying again]21.8.1 When should I try for another baby after my immune pregnancy?

21.9 Two-week wait (between ovulation and pregnancy test)21.9.1 Any do’s and don’ts during the 2ww and pregnancy?21.9.2 When should I do a pregnancy test?

22.1 Ureaplasma urealyticum22.1.1 What is ureaplasma?22.1.2 How is ureaplasma tested for?22.1.3 How is ureaplasma treated?

22.2 Uterine biopsy22.2.1 How is uterine biopsy done?22.2.2 What is it for?22.2.3 Please explain my uterine biopsy results?22.2.4 How much does uterine biopsy cost?22.2.5 Should I have a uterine biopsy?22.2.6 How are uterine biopsy problems treated?22.2.7 Which labs will do a uterine biopsy?

24.1 Weight/BMI/visceral fat24.1.1 Is it worth the effort to lose any excess weight before my treatment?24.1.2 But heavy ladies, smokers, drinkers and other people with unhealthy lifestyles get/stay pregnant all the time, so how can weight and lifestyle factors be so important?

24.2 Why?24.2.1 Why do I have immune issues?24.2.2 Why did my fertility treatment not work?24.2.3 Why did my pregnancy not continue?

1 Important noteI have put this together with the intention of reassuring and helping other FFs deal with day to day questions during their immune treatment and testing. This information has been put together by a patient and has not been reviewed or endorsed by any doctor. Some of the information is my personal opinion and may not necessarily be accepted by others – and is based on my experience of being treated by Dr Gorgy – so the protocols used by other doctors may be different and Dr Gorgy’s advice to other patients will always take into account their own circumstances so may be different to my experience. If at any time you have concerns, your consultant or your GP should be your first point of contact. I have mentioned the views and treatments of other doctors where I have become aware of them, but this FAQ is probably most relevant to patients of Dr Gorgy.

IF YOU HAVE ANY COMMENTS, SUGGESTIONS OR ADDITIONAL QUERIES, PLEASE CONTACT ME BY PM – so that I can amend this FAQ and keep it tidy. Please bear in mind that immune treatment is controversial and is not accepted by all clinics – but the purpose of this FAQ is to help ladies get through the immune treatment they have chosen to do – not to justify it or get into a debate about the evidence for it.This FAQ is in alphabetical order – so probably isn’t quite as useful to read as a ‘starter guide’ but hopefully there is some useful info in it somewhere.

2 A2.1 Abbreviations you may see in immune threads2.1.1 Are there any extra abbreviations used in immune threads?On top of the abbreviations you will often see on Fertility Friends (see here), a few extra abbreviations are commonly used in immune threads.

**for more contact details and website addresses see Resources and Links – below**

2.2 Acupuncture/reflexology/aromatherapy/massage/homeopathy etc2.2.1 Will alternative therapies help my immune treatment? (for Supplements see below) A lot of ladies find these techniques helpful. My feeling is that if they appeal to you and help you relax, then they will probably be beneficial as they may help to reduce TNFa by reducing your anxiety level, but if you are anxious about having acupuncture, it may not be particularly useful for you. There are specific protocols for fertility and some practitioners will have received more training in that than others. As far as I know, studies have not yet demonstrated that these protocols are any more successful than placebo. With regard to reflexology and homeopathy, I am also fairly sceptical, but anything that helps you relax may be helpful. Where essential oils are being used, I think its important to use a properly trained practitioner as some oils can potentially be dangerous in pregnancy and many embryologists recommend avoiding aromatic oils and chemicals around egg collection/egg recovery as they are so strong that they can penetrate the whole body including the eggs and sperm (which is why most embryologists ask you and your partner to avoid perfumes, aftershaves and other cosmetics around egg recovery and embryo transfer).

2.3 Alloimmune versus autoimmune issues2.3.1 What are alloimmune and autoimmune issues?Immune doctors classify immune problems into alloimmune and autoimmune categories (although of course some ladies will have both).

Alloimmune problems occur where the implanting embryo is genetically very similar to the host mother (usually because the genetic father is very similar to the host mother and the embryo inherits half of its genetic material from him). The immune system is always on the look out for ‘altered self’ cells because these are usually your own body cells (‘self’) but are either showing signs of cancer, damage or harbouring a virus. It is the job of some immune cells to find ‘altered self’ cells and destroy them. Having very similar genetic markers (e.g., DQalpha markers) between prospective parents is associated with higher rates of pregnancy failure and this is thought to be because the host mother’s immune system may fail to recognise the embryonic tissue and misinterpret it as ‘altered self’.

Autoimmune issues generally arise when parts of the body’s immune system are overactive, so much so that they are attacking ‘self’ tissues. For example, in many autoimmune disorders, the body attacks its own tissue e.g., rheumatoid arthritis, Crohn’s disease, thyroid diseases, coeliac disease, IBS, MS, sarcoidosis, eczema, diabetes, asthma, lupus etc. Autoimmune conditions are strongly correlated so if you suffer with one, you and your genetic family are more likely to suffer with others. Autoimmune issues can manifest at a subclinical level i.e., there may be autoimmune activity going on, but at a level which is insufficient for you to be aware of any significant symptoms.

Both alloimmune and autoimmune issues can cause problems for getting and staying pregnant.

2.4 Antibody2.4.1 What is an antibody?An antibody is a protein made by the body which will attach to a particular part of another protein (an antigen). The antigen is usually foreign e.g., part of something you have ingested, but can sometimes be something made by the body, e.g., a hormone. Once the antibody has attached to the antigen, it means that the antigen has been 'tagged' by the body, so that other body processes can recognise it and deal with it appropriately, which may mean attacking and destroying the substance which has been tagged. When you are first exposed to an antigen, the body may start to produce B cells which are sensitised ('primed') to that particular antigen and make antibodies to tag it. Recognition of the same antigen can last a long time in the body through subsequent generations of primed B cells descended from the original cells which were exposed to it, which all continue to produce the same antibody.

Antibodies themselves are not 'alive', they are only proteins.

Different classes of antibodies to the same antigen are usually produced e.g., IgA, IgG and IgM.

The immune treatment IVIG is a solution of mixed antibodies extracted from human blood.

2.5 Anti-cardiolipin2.5.1 What does having a positive anti-cardiolipin level mean?Anti-cardiolipin is a type of anti-phospholipid antibody. Having a positive test means that you have a type of acquired thrombophilia known as anti-phospholipid syndrome - see T for thrombophilia.2.4.2 Anti-ovarian antibodies - see corticosteroids 2.4.3 Anti-thyroid antibodies - see Thyroid 2.4.4 Anti-progesterone antibodies - see NK assay, CD19+5+

2.6 Appointments2.6.1 How can I see an immune fertility specialist/get Chicago tests run?If you want fertility treatment through the Care group (e.g, Nottingham, Sheffield, Manchester), or with the ARGC in London, you can have your Chicago tests run through them. If you just want tests done, you can organise it yourself by getting your blood drawn (at your GP or local private hospital) and arrange for a courier and payment to get the tests run at RFU Chicago (see RFU) – provided you have a doctor (e.g., your GP) who is prepared to be your referring doc (the one that the results will be sent to). You do need to be careful to get the right tubes (see RFU below), choose the right tests, and make sure the packaging and forms for customs are filled in correctly. If you arrange the tests without a consultant, you may also struggle to understand the results and have difficulty getting access to the appropriate treatment. This blog contains a useful guide to how to arrange to ship bloods yourself to RFU (Chicago) or Millenova (California) in the US. Its particularly good at showing you how to fill in the forms for fedex international shipping: http://www.miscarriage.co/?page_id=35

You can have an alternative set of some of the 'Chicago' tests run in the UK at a lab called RIC but the tests are not exactly the same so it is difficult to compare the costs between RFU and RIC and RIC do not offer either LAD or DQa - see RIC below.

Dr Gorgy at the Fertility and Gynaecology Academy in London will provide immune testing and treatment to patients having their fertility treatment with him, but will also provide immune testing and consultations alongside other IVF clinics (in the UK or overseas) and will consult by phone for long distance patients. It is also possible to be a long distance patient with the Alan E Beer (AEB) centre in the US or Dr Braverman in New York. There are other clinics worldwide, including the SIRM chain in the US, but I presume they only look after immune testing and treatment for their own IVF patients. The shortest waiting lists for an initial appointment in the UK are usually with Dr Gorgy. The Lister also provide some of the Chicago tests.

All the immune clinics have different offerings, and choosing a clinic is difficult because their approaches are different. Dr Gorgy probably takes the most flexible approach and listens to patients own preferences which will tend to suit patients who want to ‘take charge’ of their treatment, or want to try novel protocols proposed by other clinics, but others may be happier at somewhere like the ARGC where the approach is more programmed. The range of treatments available at different clinics also varies a lot. The Lister (Dr Thum) seem to use mainly steroids and clexane (possibly IVIG or ILs for some patients), but seem to treat more conservatively. Care seems to use mainly steroids, clexane and intralipids (and closely follows the protocols used by SIRM in the US), although will refer patients elsewhere for LIT and will prescribe Humira if patients request it after other treatments have failed. ARGC tend to favour steroids, clexane, Humira and IVIG and have just started using intralipids. Dr Gorgy uses steroids, clexane, Humira, IVIG, LIT and intralipids as well as antibiotic treatments for infections. Most clinics, including Dr Gorgy will allow you to self-refer – so you can just phone up and book an appointment.

The immunes programme at the Care group was set up and run by Dr Ndukwe (Nottingham) but he left Care to set up an IVF programme alongside Zita West (an alternative medicine practitioner) in London in June 2011. It is not clear at the moment who will be taking over running the immunes programme at Care, but there are other doctors at Care who do some immunes work, for example, Dr Patel at Manchester. At his new clinic in London, Dr Ndukwe offers immunes treatment alongside IVF etc.

Dr Amanda O'Leary at Cardiff (CMRW) started offering immunes testing and treatment in February 2011 (steroids, intralipids, clexane) according to the CMRW website http://crmw.co.uk/immunology-testing.php

GCRM in Glasgow have started offering steroids, intralipids and clexane to selected patients but don't yet have arrangements to do immune testing.

New Life in Epsom also do immune testing - mainly using RIC UK rather than RFU Chicago and seem happy to deal with patients who are TTC naturally rather than using IVF.

Trevor Wing at Natural Gynaecology can also run immunes tests using RFU Chicago.

Another possibility worth considering is having immune testing and treatment via Serum in Athens. Serum don't offer immune testing themselves, but they have an arrangement with a Professor (Dr Ekornormou - I'm not sure of the spelling - they used to use Dr Nodares but no longer do) at one of the medical universities in Athens who provides tests, consultations and treatment plans. Prior to the Greek financial crisis there was a long wait to see the Professor, but as government funding has been withdrawn, appointments are apparently available very quickly. My understanding is that he uses a laboratory in Athens for the tests so does not have to send bloods to Chicago so the results are available quickly and cost about half the price of the Chicago versions for tests including the NK assay, immunophenotype and cytokines. The arrangement is that Serum help you arrange to see the immunologist who recommends the tests you need and advises on the results (you would need to pay the immunologist directly and Serum don't receive any fee for arranging for you to see him).

Serum can do some immunology related tests in house e.g., LAD (which Serum refer to as the 'antipaternal antibody test), tests for genetic thrombophilias (MTHFR, PAI-1, Factor V Leiden, Prothrombin II etc) and standard blood tests like thyroid tests, clotting, hormones etc, infections, and most results are available same or next day.

LIT and intralipid treatments are available at Serum for a fraction of the cost in the UK (6 or even 7 days a week), and drugs such as steroids, clexane, gestone, valtrex, antibiotics etc can easily be obtained back in the UK using a prescription brought home or emailed to you from Athens - Serum are used to dealing with international clients by phone and by email. I haven't done immune testing and treatment from scratch in Athens, but my understanding would be that even with the cost of travel (provided you can find a reasonable flight cost), it ought to still work out cheaper than, say, testing and treatment with the consultants in the UK. I would expect that Serum would be able to prescribe and administer IVIG and prescribe humira (which is self-administered) for a patient that needed it, although, I would expect they would be very reluctant to prescribe ivig without a very specific reason because of their perception of the cost vs benefit of ivig and my understanding is that Serum are not keen on humira due to the lack of safety data. Paternal LIT treatment with Serum definitely works out cheaper than treatment in London. Serum are also starting to offer PBMC treatment (for implantation failure) which doesn't seem to be available in the UK yet.

Dr Mantovolous in Athens also has a well-established immunology clinic which works with the Beer protocols and operates a twice-monthly LIT clinic (Dr Tsagaris), but my understanding is that their test costs are not dissimilar to the costs in the UK.

Whoever you see, at your initial appointment, the consultant will usually go through your history and advise you on what testing to have. Ideally, you should feel that it is your choice which tests you decide to have and given the costs of testing I don’t think it is unreasonable to ask the consultant to prioritise the tests for your case. However, the more your can read and understand before your initial appointment the less stressful it will be because you can then make an informed choice and not feel frustrated at yourself later for agreeing to tests that you decide you are not so keen on or turning down tests that you later realise would have given you critical information. If you can obtain a copy of all your relevant medical records and tests to date to take with you to your initial appointment, that would probably be extremely helpful. You might want to write yourself a summary of your fertility and medical history to date and any questions you want to focus on to get the most out of your appointment, but at an initial appointment, you may find that the consultant will want to defer some answers until he has completed any testing.

At follow up appointment(s), you will go through your test results, recommendation for treatments and any ongoing issues during your fertility treatment and pregnancy.

The costs of consults are in the UK are around £100-300 ($350-650 for phone consults with Braverman in the US), and the immune tests sent to specialist labs like RFU are very expensive e.g., £350 for 1 test (of which you may be recommended to have a number of different tests, and later, retests).

Bear in mind that different docs have preferences for different tests and may be dismissive of tests run by other docs e.g., some clinics use the CD69 NK test run by RIC in the UK - but Gorgy, Care and ARGC don't seem to trust that test and rely on the NK assay run by RFU in the US. A few docs rely only on the NK uterine biopsy e.g., Dr Quenby in Liverpool - but other docs feel either that the biopsy has limited value or that the blood tests are just as informative. Either way, it is not always easy to change immune docs without incurring extra expenses for additional tests/retests.

The treatments prescribed like IVIG, Humira, LIT and intralipids can be very expensive (IVIG and Humira are expensive drugs to manufacture, LIT is labour intensive, and even the cost of intralipids can mount up due to the nursing required). Different clinics can negotiate different fee arrangements with drug companies and with labs and they also charge different mark-ups on tests and drugs, but most of these costs go to the drug companies and to the labs which is worth bearing in mind if you are trying to understand whether the fees charged for consultations and advice are reasonable. The costs do not necessarily stop when you get pregnant as you may need further consultations, retests and treatment during pregnancy. Where you are having your IVF treatment together with your immune treatment at the same clinic, some clinics will not charge extra for further advice on your immune treatment, but, where you don’t have an ongoing treatment arrangement because you are TTC naturally or are having your IVF treatment elsewhere, in order to answer your ongoing questions, your consultant may need to review your notes or provide you with additional medical advice, so will expect to charge for this.

Please be aware that testing and treatment takes time so if you decide to see an immune consultant shortly before starting your fertility treatment or, even when you are in early pregnancy there may still be treatment options that may help but you might not have time to fit in all the immune treatments – although of course you would have the option of delaying your fertility treatment if that is what you decide to do.

If you do want to have your Chicago tests run on your visit to Dr Gorgy you need to book an appointment on a Monday/Tuesday/Wednesday morning early enough so that you can go to TDL (two doors away) after your appointment and get the blood drawn, probably before 1pm (although cut-off time does vary depending on fedex, flights, bank holidays etc). If it is close to a US or UK bank holiday, it is best to check in advance that there will be a TDL fedex run on that day. The TDL department that deals with Chicago is called ‘Referrrals’ and TDL’s website (www.tdlpathology.com) provides information on their opening hours etc. If you are just making a trip to have bloods done, you can arrange to pick up the referral form from Dr Gorgy’s receptionist on your way to TDL without needing an additional appointment to see him. Alternatively, you can send bloods by post, by prior arrangement with Dr Gorgy’s receptionist (see the info on specific tests below).

Arguably, if you are doing 'normal' fertility treatment there is no extra value in having early blood tests, but if you are having immune Tx, it is very useful to have 2 early blood tests roughly 48 hours apart (if they are not 48 hours apart you can use a bHCG calculator to work out the equivalent 48 hour values).

If the rise is at least 66% in 48 hours that is excellent and it means that any expensive further immune Tx that you are due to have e.g., ivig drips is justified and not wasted on a non-viable pg.If the rise is marginal, your consultant might advise an urgent drip (and/or an urgent scan to check for viability and to exclude a dangerous ectopic pregnancy)- then if the rise improves, hopefully the pregnancy will recover and survive, but if, unfortunately it does not, you have gained very valuable information that confirms the problem probably was immune attack and that you need more drips earlier etc next timeIf the rise is poor, you know that it is probably not worth having another expensive shot of ivig etc, and you know you need to be scanned and monitored in case of ectopic pregnancy to avoid risks to your health and your tubes.

3.2 Bleeding in pregnancy3.2.1 I am spotting/bleeding in pregnancy – am I miscarrying?According to Dr Sher at SIRM, at least a third of fertility treatment ladies have bleeding in pregnancy, and at least 50% of the time, the pregnancy may continue even if the bleeding is heavy and includes clots. Spotting is often caused by irritation of the cervix due to increased progesterone and doesn’t threaten the pregnancy at all. It may be possible to confirm whether spotting is purely due to cervical irritation by a speculum (internal) examination but it may be hard for the doc to be sure.

3.2.2 I am spotting/bleeding in pregnancy – what should I do?If you are experiencing pain and/or bleeding and you have not already had your first scan to confirm that the pregnancy is intra-uterine (in the uterus), you should seek urgent medical help to rule out ectopic pregnancy. If you are bleeding more heavily than a normal period, you should seek medical help to rule out haemorrhage. If you are Rh- and your partner is Rh+, you should also seek prompt medical advice on whether you need an anti-D injection (this may depend on the amount of bleeding and how far into pregnancy you are, as well as the doc’s own views).

Generally though, the most important thing for an immune Tx lady is to rest (preferably with your feet elevated) and keep hydrated. If you are past 6.5 weeks pregnant, then if you can get a scan at your local EPU/EPAC you will be able to confirm whether the pregnancy is viable and find out if there is a subchorionic haematoma (like a bruise between the placenta and the lining of your uterus) that is causing the bleed or not, but there is currently no treatment in early pregnancy that your local hospital can provide that will change the outcome. Any doctor or A&E should be able to perform a speculum (internal) examination and confirm whether your cervix is still closed – if your cervix is closed then it’s a good sign but not definitive so its debatable whether you should rush to ask for this. If you call your immune consultant he may suggest you increase your progesterone or swap from taking pessaries vaginally to anally, for example, and if you have not been able to get a scan, he may recommend you try to get one, as if there is a haematoma it may be immune related and he may suggest an urgent drip (IVIg or Intralipids) to calm your immune system. If you are currently taking clexane and/or aspirin, your consultant may suggest stopping it until the bleeding stops – but the advice will differ depending on the severity of any clotting issues and the doctor’s own views.

3.2.3 Will bed rest help the pregnancy if I am bleeding/spotting?Many doctors would say it doesn’t make any difference, but Dr Gorgy and Dr Sher do tend to recommend rest and hydration for immune patients experiencing bleeding in pregnancy. This makes sense because bleeding may be caused by subchorionic haematoma – and studies have shown that, at least for large haematoma, bed rest is associated with an improved live birth rate.

3.3 Breastfeeding3.3.1 Why should I breastfeed my immune Tx baby?

formula milk costs about £8 a packet and each packet doesn't last very long - and there is the cost of buying bottles, sterilizing, endless washing up and having to think about making up feeds everytime you go out

breastfeeding has been proven to give numerous health benefits for baby including fewer episodes of vomitting, diarrhea, ear, chest and urine infections, meningitis, septicaemia, - which could mean less emergency time off work for you as well as a happier, healthier baby

autoimmune tendencies run in families and breastfeeding is thought to improve development of the thymus gland (where immune cells are matured) and reduce the risk of autoimmune disorders in childhood e.g., asthma, excema, arthritis and later life e.g., insulin dependent diabetes, Crohn's disease, ulcerative colitis, coeliac disease etc. The risk of type 1 diabetes is thought to increase by exposure to antigens e.g., insulin, from cow's milk (in formula) before baby's immune system is able to cope (from about 6 months).

breastfeeding reduces baby's chances of obesity in later life which reduces the risk of heart disease, strokes and several cancers

because of the reduced risk of illness, even in europe and the usa, breastfeeding is thought to reduce the risk of infant death in the first year by 3-20%

breastfeeding is associated with better scores on intelligence and physical development tests

breastfeeding is thought to reduce your chance of developing rheumatoid arthrits and diseases associated with obesity

immune tx babies are 'extra special' because most of us have been through years of longing, disappointment and all our savings to get the chance to hold them - we'd be crazy not to do our utmost to give them the best possible chance for their future

3.3.2 Can all babies breastfeed? Can all mothers make enough milk to breastfeed?

Only a tiny percentage of mothers cannot physically produce all the milk their babies' need - even for twins and triplets. However, not all babies take to breastfeeding automatically, particularly babies who suffer from jaundice or other medical conditions and full milk production naturally takes a few days to get established. This is not a problem for a strong, healthy baby, but can be more of a concern for a baby with medical problems who needs calories quickly.

Establishing a milk supply is controlled by the hormones oxytocin and prolactin which are stimulated by the action of baby suckling. If a newborn is too weak to suckle, or natural frequent feeding is interrupted by medical procedures or too many visitors in the way etc this can result in a vicious circle of not enough suckling, so not enough stimulation, so not enough milk, not enough calories, leading to an even weaker suck. Unless baby can be persuaded to suckle, the remedy for this is to start expressing milk at the first sign of any feeding problems, consistently and very frequently (at least 8 times a day including during the night) using a hospital grade pump.

All milk expressed can be given to baby by syringe and the more milk that is pumped, the faster milk supply will increase making baby's chance of learning to suckle quickly greater. Even if baby still does not take to the breast, all the time they are receiving expressed milk they are getting the immune benefits, and hopefully getting stronger so that eventually they will suddenly decide that fresh 'hot' milk is worth the effort of sucking.

Rates of breastfeeding in the UK have historically been very low so expertise in encouraging breastfeeding for babies who do not take to breastfeeding immediately in the NHS is very poor because midwives are used to dolling out bottles of formula rather than thinking about suggesting the hospital pump quickly enough. Despite their job titles, NHS 'breastfeeding champions' often have a lot less experience and training than private lactation consultants (available through the NCT or La Leche league). If you find yourself in the first few days after baby's arrival and things are not working out for you and baby, my suggestion would be to phone your local NCT or La Leche League breastfeeding expert, if necessary whilst you are still in the maternity unit - and don't rely on the NHS midwifery staff - they turnover patients so quickly, most have almost no real experience of establishing breastfeeding except for really easy babies who can do it anyway.

The most useful advice I can give is to say that if it feels wrong to you, regardless of what you are being told to do, it probably is and so you should try a different angle/position etc, and whatever position works for you and baby is ok - you do not have to stick to any rules for perfect position or rules like 'bring baby to the breast, not breast to baby' - if bringing breast to baby works better for you and baby, then its fine. There are no marks for style only for comfort and a healthy baby! The only important rule is that if baby is not suckling at least every 2-3 hours within a couple of days, get pumping in the meantime to ensure your milk production kicks in and keep pumping until baby is ready for the breast. Anything that interrupts frequent suckling in the first 4-6 weeks can temporarily shut your supply down which isn't a problem for a strong, healthy baby but can become a problem if a less healthy baby loses the energy to suck enough to kick start your hormones.

It is not unheard of for babies to take the breast for the first time when 2 or 3 months old if they are given the opportunity to (some mums decide to switch to breastfeeding late after formula feeding or adopt an older baby - breastmilk can be induced at any point after a successful pregnancy by a combination of frequent pumping, medication e.g., domperidone, and suckling (relactation) and can sometimes be induced in adoptive mums who have never been pregnant.

Milk is produced on a supply and demand basis with a bit of a timelag, so if you want to fill your fridge or freezer with extra supplies of milk, pumping frequently for a few days will boost your supply so that after a few days you can start producing 2-5 times as much as your baby can drink. When you want to reduce your supply, do it gradually to avoid mastitis and a sudden drop in your hormone levels leading to a total cessation of milk, so, for example, if you have been supplying several times your baby's needs and want to drop down to lower quantities, gradually pump less for a few days rather than suddenly stopping.

If you want to insure against any initial supply problems, you can hand express early milk (colustrum) before baby arrives (from about week 35-36) and freeze it to take it to hospital with you (in an icebox), so that baby has an instant supply in the hospital freezer. 2.5ml or 5ml syringes are ideal for 'hoovering' up the drops of colustrum from your nipple as you express them - your hospital should be able to supply you with syringe caps in advance. Each syringe should be labelled with your name and the date of expressing and then placed in a plastic bag and frozen immediately until needed.

4.2 Chlamydia Trachomatis4.2.1 What is Chlamydia?It is an extremely common STD (something like 1 in 7 of the normal population have it and it is likely to be even higher in ladies with ‘stubborn’ infertility). It is well documented that it increases the risk of miscarriage, premature birth, stillbirth and causes infections (mainly eye and lung) in newborn babies. It is also proven to cause tubal blockage and scarring leading to adhesions, ectopic pregnancy, hydrosalpinges (swollen, fluid filled tubes) and resulting infertility. Usually it shows no symptoms, but occasionally it may cause PID (pelvic infection associated with pain and fever). The degree of scarring is probably influenced by your genes – some women will have no scarring whereas others will have very severe damage. Chlamydia can cause infertility and immune responses even where tubes are undamaged by raising the level of inflammation and immune activity in the uterus making it a hostile environment for the embryo. Many younger women give birth whilst carrying Chlamydia and are completely unaware of it, but its effect on fertility may become more of a barrier to getting pregnant as you get older and are generally less fertile and your body starts to switch priority from fertility to immune defence.

Before antibiotics were available, Chlamydia trachomatis (C trach) used to be a very common cause of blindness which was commonly passed from a mother to her baby. Eye infections with C trach have been shown to be transmitted in poorly chlorinated swimming pools and some studies have shown that eye infections can result from 'autoinnoculation' (i.e., touching the eyes with fingers that are contaminated with genital secretions containing C trach. At least one study has shown that C trach can survive on hard surfaces for about 45 minutes, so in theory, it could be contracted by touching a contaminated surface then touching the eyes. However, almost all cases of genital chlamydia are contracted though sex. C trach has also been implicated in some cases of arthritis as it has been detected in the tissue of inflamed joints.

4.2.2 How is Chlamydia tested?The most common tests are vaginal/cervical swab test by PCR (DNA fingerprinting) for women. Urine PCR is also available for women but is not supposed to be quite as accurate as the swab. In men, urine PCR is the most common method. Urine and swab PCR should be available to you free through your local GUM clinic (or your GP).

A Chlamydia antibody test (CAT) is also available – sometimes through your GP, IVF clinic or private lab. This is a blood test to see if you have had a Chlamydia infection in the past. It cannot tell you whether you still have Chlamydia or how long ago you had the infection. Studies suggest that the antibodies persist for at least 5-8 years but the test is still relatively new for follow up studies to have been completed and some docs don’t value the test because it can’t give any information about your current Chlamydia status.

In men, the most conclusive test for Chlamydia is probably a semen PCR test because that should pick up on Chlamydia anywhere in the male reproductive tract. A semen culture test should also pick up on Chlamydia anywhere in the male reproductive tract, but is slightly less accurate than a PCR test. Most labs will do a sensitivity test on any bugs that are found on the culture to determine which common antibiotic is most effective at killing the bugs which are present.

Many doctors would say that if the swab PCR are negative then there is little chance that a woman still has Chlamydia, but there are a few docs who say that this is not the case, as Chlamydia is a very complex microorganism which can migrate up the genital tract (and no longer be detectable by vaginal swab) to cause periodic inflammation and immune activity in the uterus leading to implantation failure or miscarriage. Consequently, some docs/clinics say that only a sample from the uterus will be conclusive in establishing whether Chlamydia is present there or not. PCR of a uterine biopsy sample is logically the most definitive way to test, but the Locus Medicus lab in Athens have pioneered the testing of a sample of menstrual tissue by PCR. This avoids the discomfort of a biopsy. You collect a sample of menstrual flow (on around day 2 of your period) at home which you have couriered to the lab. Dr Gorgy’s clinic will provide instructions, a sample bottle and fedex details for you to do this, or you can do it with Serum or direct with the lab. The easiest way of collecting a sufficient sample is to use a mooncup overnight. The sample can be refrigerated until fedex come to collect it. The sample can be sent in any small, sterile container (and is usually wrapped in foil and then bubble wrap). To ensure that the sample stays liquid until it is dehydrated by the lab, the container needs to contain a few drops of sterile saline (e.g., contact lens saline), but samples using cooled boiled water have also been accepted by the lab. According to the lab, samples which are about a week old by the time they are received are still viable.

4.2.3 How could I test positive for Chlamydia when I have tested negative on other tests?If you have previously had the vaginal swab or urine test, its possible that you were still infected with Chlamydia in your uterus at that time as the swab can only sample any bugs that are present down in the vagina.

4.2.4 How could I test positive for Chlamydia when I have previously had antibiotics for it?The most commonly prescribed treatment is 1g of azithromycin (zithromax) or 7-10 days of doxycycline (vibramycin). Even on studies of uncomplicated genital Chlamydia (not in situations where Chlamydia may have been present for many years), a small proportion of patients were shown to still have Chlamydia (by swab test) even after these antibiotics. A number of docs are suggesting that for patients who have previously tried these common short courses of antibiotics, a longer course is required to deal with the infection. It is also possible that if you have active C pneumoniae infection that would cause a positive result on the greek test.

4.2.5 Why should I have the Chlamydia test?Patients who are at high risk of having Chlamydia include anyone who has a previous history of ectopic, tubal blockage, hydrosalpinx, PID, uterine scarring or known history of infection in themselves or their partner. Some docs believe that a thin (on ultrasound) or inflamed (on biopsy or laproscopy) uterine lining (or cervix) may be another indicator of long term infection. It is still possible to have Chlamydia without any of those risk factors though. If both you and your partner had only EVER had sex with each other, its unlikely that you would have Chlamydia but vertical transmission from the mother is still possible. Many doctors would dispute the idea that a person could have had silent Chlamydia all their life.

Anecdotally, ladies who have detected Chlamydia using the greek test and followed it up with antibiotic treatment have reported

It is unlikely that all abnormal Chicago results are caused by undiagnosed Chlamydia, but it does seem that a proportion of them are, and given the test and the antibiotics are relatively inexpensive compared to, say, IVIG, it seems to be good value for money to me to explore this avenue of testing in priority to other aspects.

4.2.6 What do I need to know about the Chlamydia test by menstrual blood PCR?It is a new test and not yet accepted by most of the medical community. No formal scientfic studies have been published using it yet. It uses a similar method to the standard tests (i.e., PCR) but using a patented method with different reagents (the reagents used in other patented methods in the UK and elsewhere were developed for blood-free samples (urine, swabs, semen etc) and are sensitive to enzymes in blood and cannot be used on menstrual samples. The greek laboratory, Locus Medicus, hold the worldwide patent on this new test.

Like all PCR tests for Chlamydia, it cannot distinguish between different bugs from the Chlamydia family (but other than Chlamydophila pneumoniae (which causes pneumonia)), the other Chlamydiae are almost unknown in humans. Like C trach, C pneumoniae reproduces by infecting white blood cells, and, in theory, a menstrual blood sample could contain C pneumoniae as well as C trach. However, Serum believe that the majority of positive greek tests seen in infertility patients are due to C trach, and, in the event that there is infection with C pneumoniae rather than C trach, I think it is still possible that C pneumoniae could contribute to infertility by, for example, increasing NK activity and TNFa. C pneumoniae is also implicated in alzheimers, pre-eclampsia, heart disease and strokes. The antibiotics recommended for C trach are similar to those recommended for C pneumoniae.

Locus Medicus will provide an estimate of the concentration of Chlamydia bugs in the aliquots of sample that they test in the format of, for example, 1.8 x 10^3 (which is 1,800 - anything which is x 10^2 or 10^3 is a fairly low concentration of bugs) or 3.5 x 10^8 (which is 350,000,000 - anything which is x 10^8 or 10^9 is very high - anything which is x 10^4 or 10^5 is, I suppose a moderate result - whereas anything x 10^6, or x 10^7 is fairly high). However, it is important to remember that PCR is not accurate as a quantitative test so it would be misleading to read too much into the estimate provided. Most labs do not attempt to give quantitative measurements on PCR tests for this reason.

As with all PCR tests, the test cannot distinguish between live bugs and dead bugs. Therefore, if you test too soon after taking antibiotics, you may still get a positive result, even if all the Chlamydia bugs are dead.

4.2.7 How much does the Greek Chlamydia test cost?Currently, Dr Gorgy charges £200 including the instructions and sample bottle (this does not include a consultation if your test comes back positive). Depending on exchange rates etc it MAY be cheaper to contact Locus Medicus direct (apparently its about 90Eu at the moment) or arrange the test through Serum in Athens but you will have to sort out the post (post is much cheaper than fedex, but can be unreliable - it may be worth keeping an extra sample in your fridge in case the first one goes missing in the post) arrangements yourself and if positive, find a consultant who will prescribe the antibiotics to you (although Serum Athens have helped ladies in the past by sending medication by post from Greece). You can obtain a sterile urine sample bottle from most (large) pharmacies for about £0.50. According to Locus "In order to charge your credit card we need you to send us a formal request allowing us to charge it, including the number of the card, the security code, the name of the owner, the expire date and your signature".

4.2.8 How long will the results take to come back?Results from Locus Medicus are normally back within one week. If you have the test via Dr Gorgy, you will need to contact his clinic for the result. If the result is positive, Dr Gorgy will want you to arrange a face to face or telephone consult to speak to you personally about the result as he will need to advise you on your options and prescribe antibiotics. Dr Gorgy will provide you with a private prescription for antibiotics. If you shop around, it will probably be a similar cost to asking your GP to provide an NHS prescription and less hassle (bearing in mind that the protocol uses multiple drugs and is for both partners and there is an NHS charge for each drug). I always found Rigcharm pharmacy in Shadwell, London, or Fazeley pharmacy to price quite competitively and does mail order.

If you choose to deal directly with Locus Medicus, you will either need to see if your GP is prepared to prescribe the recommended antibiotics on an NHS prescription, arrange a consult with Dr Gorgy for a private prescription, contact Serum Athens who can put you in touch with a greek pharmacy (you do not need a prescription to buy these antibiotics in greece), or, apparently, you can purchase azithromycin and doxycyline antibiotics using an online consultation form from www.doctorfox.co.uk (at a markup). Azithromycin is sold for STDs and doxycycline as an anti-malarial drug. Apparently, if you email your results and a brief medical history to Peny at Serum (see Resources and links), for a phone consult charge of 100Eu, she can arrange to email you a prescription which pharmacies like Rigcharm in London and Fazeley in Derbyshire will accept by email. Then you can have the antibiotics posted to you. Some UK pharmacies may accept a printout of an emailed prescription but some will insist only on a signed original.

4.2.9 What is the treatment for Chlamydia?The protocol most commonly used lasts for 25 days and is something like:

Day 1: 4 pills of Zithromax 250 mg = 1g, all together & with empty stomachDay 2 : NothingDay 3-7: Vibramycin 100mg (Doxycyline), 2 tablets/day, one in the morning and one in the eveningDay 8: 4 pills of Zithromax 250 mg = 1g, all together with empty stomachDay 9-24:Vibramycin 100mg (Doxycycline), 2 tablets/day one in the morning and one in the eveningDay 25: 4 pills of Zithromax 250 mg= 1g, all together preferably with empty stomach

plus: Omperazole 20mg first thing in the morning to prevent nausea (particularly on the zithromax days).The azithromycin is the same dose as commonly used in UK GUM clinics (but in this protocol it is used twice). The doxycyline is the same dose as commonly used but in this case its taken for 21 days rather than the more common 7-10 days. Bear in mind that for some conditions, antibiotics in doses like these are commonly taken for months – but on the other hand, antibiotics should never be taken unnecessarily because of the risk of increasing antibiotic resistance – so it would not be a good idea for these longer courses to be taken routinely for everyone who picks up Chlamydia.

Absorption of doxycycline is inhibited by free calcium (iron, magnesium and other metals as well as folic acid) – therefore its important to avoid taking supplements containing these within 2 hours of doxycycline – and to avoid milk, cheese, yoghurt, and tinned fish with bones in (because of the calcium content). Its worth knowing that despite being dairy, butter is low in calcium so you can start your day with buttered toast (although without milk in your coffee). Most brands of soya, oat, rice milk etc have added calcium but one or two varieties are low in calcium. Doxy is less harsh on your stomach if you take it after a substantial meal with a big glass of water. Do not lie down for at least half an hour after taking it.

Most ladies prefer to take a proton pump inhibitor (non-calcium, non-magnesium ant-acid) like omeprazole (20mg on prescription or 10mg over the counter) to reduce nausea. All antibiotics may give you an upset stomach. A good quality non-dairy probiotic tablet (look for something with a high lactobacillae count e.g,. 30 billion per tablet) may help some ladies.

Both partners need to take the course of antibiotics and use barrier contraception until they are certain they have cleared the Chlamydia, although anecdotally, it does seem easier for men to clear the infection than ladies – so if you can only persuade your partner to take a standard course of antibiotics that would be better than nothing – but Dr Toth, for example, insists that heavy duty courses of antibiotics are absolutely necessary for both partners. Additionally, (re)testing in men is cheaper than for women and can easily be done in the UK e.g., semen PCR Chlamydia test through TDL in London.

There are alternative protocols available. Dr Toth in New York, for example, prescribes an arduous antibiotic protocol involving IV antibiotics (given with an ambulatory pump initially for 10 days), uterine antibiotic washes (lavages) and prostatic injections for men. SERUM and Dr Gorgy are continuing to investigate courses of antibiotics to take during fertility treatment and pregnancy, particularly for ladies who fail to clear Chlamydia after the 25 day course.

For example, the following 7 week course is sometimes used by Dr Gorgy:

Other ladies who have failed to clear Chlamydia after the 25 day course have successfully used these regimes alongside their IVF:

day 1 of IVF cycle 1g azithromycinday 2 until ET 100mg doxycycline tabs with breakfast and with supper (avoiding calcium rich foods)ET until pregnancy test clarithromycin 500mg twice a day (or azithromycin 500mg once a day)from pregnancy test day - 5 days without antibiotics followed by 5 days with clarithromycin 500mg twice a day (or 500mg azithromycin once a day) followed by 5 days without antibiotics then 5 days with clarithromycin (or 500mg azithromycin once a day) - repeated until about 7(-12) weeks of pregnancy; or

day 3, 6 & 9 of the IVF stimulation- 1g azithromycin

However, SERUM seem to use an 'in-cycle' protcol for most ladies who test positive for chlamydia, rather than trying to erradicate chlamydia before IVF (starting 12 days before your period is due - and using barrier contraception):

then from bfp 5 days on and 5 days off clarithromycin (or 500mg azithromycin) until about 8 weeks of pregnancy

After the positive pregnancy test, Serum seem to prefer to recommend clarithromycin, erythromycin or azithromycin rather than doxycycline, although up until then, doxycycline may be the preferred option for ladies with immune issues because it has some proven NK suppression activity.

For ladies who test positive for mycoplasma as well as chlamydia, serum seem to substitute erythromycin instead of doxycycline.

The standard treatment for ‘uncomplicated genital chlamydia’ in the UK from your GP or GUM clinic is either 1g of azithromycin or a 10 day course of 100mg (twice a day) doxycycline. So basically, the Serum 25 day protocol uses the same concentrations of drugs but you take them for longer. Chlamydia has a complicated lifecycle involving an infectious 'spore like' EB (elementary body) stage, a transition stage and a replicating stage (reticulate body - RB) stage. Some doctors believe that different antibiotics are more effective at dealing with Chlamydia 'bugs' in different stages of their lifecycle (at one point in time, in the body, some of the chlamydia infection will be in each of the different stages) so that a combination of antibiotics that work in different ways may be more effective in erradicating an infection than taking one antibiotic with a single mode of action.

The standard protocol has been tested in large clinical trials and it has been proven to eliminate most (but not all) cases of ‘uncomplicated genital chlamydia’, but many of the ladies who have sought help at SERUM have previously had the standard protocol antibiotics, are likely to have originally been exposed to Chlamydia several years before, and additionally many of them have tested negative for Chlamydia (by vaginal swab) suggesting that their infections are a) no longer uncomplicated and b) resistant to the standard courses.

Antibiotics including doxycycline are commonly used by clinics around the world during fertility treatment despite there being some concerns about their use close to pregnancy and manufacturers’ warnings not to use in pregnancy. However, in the case of doxycycline, the evidence for any risk to the baby is very limited and the risk is thought to mainly be in taking it during the 2nd and 3rd trimesters as it affects bones and teeth. In general, no doctor recommends taking antibiotics in pregnancy (even in very early pregnancy) due to either lack of safety evidence or slight concerns about the evidence that is there, unless the risk of not taking antibiotics exceeds the risk of taking them. We would therefore all prefer not to be taking any of these antibiotics during our treatment or in early pregnancy if we didn't need them, however, some of us seem to find that we cannot get/stay pregnant without them presumably because we do have an infection and are therefore prepared to take the (hopefully tiny) risk of taking them.

4.2.10 When should I retest for Chlamydia after treatment?The usual advice is to wait six weeks after finishing the antibiotics, which ideally means you should allow for one period after finishing the antibiotics before you retest on the second period. This is because the PCR test cannot distinguish between live bugs and dead bugs and the first period may contain tissue which includes dead bugs which may give you the extra stress and expense of retesting on your following period just to be sure whether a positive result is genuine. Ideally both partners should retest at the same time, but some docs believe that women are more likely to harbour a resistant infection so, as long as you have been continuing to use condoms until the female partner is retested and have both of you have had the full course of antibiotics, it is likely (but not guaranteed) that if the female partner has cleared the infection the male partner will have too.

Bear in mind that some ladies are choosing not to retest, either because it doesn't fit in with their fertility treatment timescales or because given they will want to be taking antibiotics during treatment and early pregnancy anyway (because of the worry that the infection may not be completely erradicated), they feel there is no point in having a retest.

4.2.11 Do I have to clear Chlamydia before I can cycle?Opinions seem to differ. Dr Toth for example would be likely to recommend very aggressive treatment preconception and continuing periodically throughout pregnancy. Previously, SERUM were recommending that the 25 day course (see above) was repeated several times if the retest result kept coming back positive, which did seem to occur more often if the estimated concentration of Chlamydia in the first sample was very high, but apparently they have recently had increasing success with prescribing the 25 day course pre-conception and then following that up with additional antibiotics during fertility treatment and pregnancy (mainly Clarithromycin). Personally, if Chlamydia is diagnosed I would try to clear it before the fertility treatment as it would be preferable to ensure that the embryo is not exposed to it, but if pre-conception antibiotic treatment failed, I would have no qualms at all about using antibiotics in pregnancy if that is what it took to get/stay pregnant as long as I could avoid tetracyclines (e.g., doxycycline) in the 2nd and 3rd trimesters. I've also come over the view that I would rather take antibiotics during my treatment and early pregnancy in any case just to be sure I have done as much as possible to avoid any chance that the infection has not been erradicated completely.

4.2.12 My partner doesn't want to take all these long courses of antibiotics. Does he have to?

You do want to make sure your partner is free of chlamydia before you have unprotected sex again to avoid reinfecting you and because an infection might affect his sperm count etc. However, he MAY find it easier to clear the infection than you do and may therefore need fewer drugs to do it. If he doesn't want to take any medication at all, you could ask him to have a semen chlamydia test by PCR to try and be as sure as possible that he is not infected, and then avoid unprotected sex until you are sure that you are clear of chlamydia. Alternatively, he might decide to take a standard short course of antibiotics e.g,. the 1 shot azithromycin (as this may be all he needs to take to clear chlamydia) and then wait for 4 weeks and then test using the semen chlamydia test by PCR. Unfortunately, there is no way to know for sure how aggressive his antibiotic treatment needs to be without trying it and retesting, but a semen PCR test, in theory, may be able to pick up an infection in the prostate or testes whereas a urine PCR may not.

4.2.13 Why doesn't everyone take these antibiotics just in case of Chlamydia infection?

It would not be sensible for patients to take antibiotics if they do not have Chlamydia (or some other infection that is making it hard to get/stay pregnant). It would lead to more cases of antibiotic resistance (more bugs for which there are few/no effective antibiotics anymore). Even for patients who contract Chlamydia, short courses of antibiotics are supposed to be effective so long as they are taken promptly after contracting the disease. As an infertility community, we can expect to have more problems with infections than most other ladies who get and stay pregnant easily.

4.2.14 How can I do the menstrual blood test if I am not having periods?

An easy way to get a sample for the test would be to build up your uterine lining using progynova/cyclacur (estrodial valerate) - an HRT medication, and then after 21 days, stop the medication to induce a bleed which can be tested. Using a birth control pill would do a similar job but there could be a slightly higher risk of a false negative as lining growth is not as thick under the BCP and therefore not as close to the sort of lining you would have once you start fertility treatment.

Alternatively, you can have a uterine biopsy sample taken, or a sample of the blood after hysteroscopy.

4.2.15 Should I have a hysteroscopy to deal with scar tissue that may be left after having chlamydia?

If you do have a lot of scar tissue and filmy adhesions following chlamydia, it could significantly reduce your chances of live birth, but the degree of scarring is very variable as some ladies will have a lot of scar tissue but others will have none. Furthermore, Serum seem to regard the slightly thickened, slightly less vascularised lining tissue that most other doctors regard as looking perfectly normal in older women, as unhelpful to getting pregnant as they feel that a very gentle D&C (during hysteroscopy) together with some small cuts to the lining (see endometrial scratch biopsy) can encourage new tissue to grow which has a better blood supply to give an improved chance of implantation for the next 2-3 cycles.

I would suggest that the following are indicators that a hysteroscopy might be a good idea:

never having had a live birth, or having a long period of infertility since a live birthhaving thin/patchy linings on ultrasound scan and/or having skimpy, mainly brown periods rather than normal, profuse red blood, or brown bleeding either side of your period. Brown blood is oxidised (old) which means it has taken extra time to make its way down which could mean that its been held up by scar tissue.having blocked/twisted tubes or a history of ectopic pregnancy - which is an indication that you have scar tissue in the tubes and presumably are at higher risk for scar tissue in the uterushaving a known history of adhesions and scar tissue

Conversely, there is less likely to be significant scar tissue if you have always had good linings for IVF, have normal, profuse, red periods that start and stop sharply at the beginning and end of your period, have unblocked (patent) tubes and have either recently had a baby (which would tend to suggest that scarring should not be so severe/longstanding as to be preventing implantation), or have had a recent diagnostic hysteroscopy that has confirmed you do not have scar tissue.

The pioneers in this field are SERUM in Athens, and I have heard nothing but consistently glowing feedback about them. So I would suggest that ladies who test positive for chlamydia on the greek test, strongly consider a consult with SERUM with a view to arranging a surgical hysteroscopy through SERUM. N.B., when comparing prices for hysterocopy from different doctors, make sure you are comparing like with like. A basic ('office') diagnostic hysteroscopy will mean a shorter surgical slot as the doctor is aiming to just look at your uterus and flush with a little fluid and gas, whereas, with a full surgical hysteroscopy, the surgeon is anticipating spending longer with you and aiming to surgically cut out all scar tissue/fibroids/polyps in your uterus (and your tubes) using tiny instruments inserted up through your cervix and possibly to do endometrial scratches and a gentle D&C. If there is an expectation of endometriosis, you would need a surgical laproscopy combined with a hysteroscopy as the surgeon cannot cut away endometriosis and adhesions that are on the outside of the uterus and tubes (e.g., on the ovaries) without making keyhole cuts into your belly (laproscopy) - only the inside of the uterus and tubes can be reached through the cervix (hysteroscopy).

4.3 Clexane (lovenox), fragmin, aspirin and other blood thinners

4.3.1 What are heparins? What are they used for in fertility treatment?Low molecular weight heparins like clexane and fragmin are used to prevent blood clots. In fertility treatment they are used to prevent the microscopic blood clots in uterine tissue that may compromise growth of the uterine lining or cause miscarriage by preventing sufficient blood flow reaching the embryo. A low dose (e.g., 20-40mg) is commonly prescribed for minor clotting issues and/or elevated NK activity and/or to improve blood flow to the uterine lining. Higher doses (e.g., 60-80mg) are prescribed where significant (e.g., Factor V Leiden), or multiple clotting issues are identified. Low molecular weight heparins are chosen for fertility treatment because, although they are more expensive, their results are very predictable and therefore less likely to cause bleeding and less likely to need monitoring than ‘regular’ heparins.

4.3.2 How do I take clexane?Clexane is administered as subcutaneous injections, usually into a ‘fold’ of belly skin (in a similar way to FSH injections). It almost always comes in prefilled syringes with the needle already attached (covered by a grey cap). Some clinics prescribe two shots per day, but if there is only one shot per day, its generally advisable to take it in the morning, just in case you ever need to do a blood test for heparin levels (as these have to be done 2-3 hours after your daily shot). It is best not to advance the time of your shot by more than two hours per day – so unless your clotting issues are severe, if you forget your shot, take it when you remember, and then make that your new daily time (if necessary taking it two hours earlier each day until you get back to the time you want). Administering the shot slowly and not rubbing the injection site may help to limit bruising – and make sure to move to a new spot each day – don’t inject into an existing bruise. Don't exclude the air bubble in the clexane syringe - tap it up to the plunger end so that it goes in last and it will help give some protection from bruising and will make sure you get the full dose injected. Some ladies say that icing the site helps.

Personally, for all injections I use pre-injection wipes (cheaper from medical supply shops online than from high street pharmacies). I also keep a pack of cotton wool (make up remover type) pads handy in case there is a spot of blood to wipe that. In case I have to do injections in the car, for example, where I can’t wash my hands, I have a small bottle of alcohol gel (but washing your hands is preferable).

If you are skinny, you may need to jab at a 45 deg angle in order that the shot still goes just under the skin. If you get horrendous bruises or it hurts intolerably, think about:- making sure you aren't rubbing the skin - using xylocaine spray or emla to numb the skin - injecting at 45 deg if you are skinny (more like 90 if you are, erm.. well padded)- only pinching the fold of skin you are jabbing as loosely as you can - not pinching at all, but just gently stretching the skin and then jabbing at 45 deg- trying not to jab too close to an existing bruise- getting a clean syringe and injecting the whole jab into the barrel of the syringe, then fitting a very fine needle and using that instead (this may particularly help if you get a clexane jab that has a particularly blunt needle)

4.3.3 When do I start and stop clexane?Dr Gorgy tends to start clexane (often on a reduced dose, initially) on day 5/6/7 of your cycle/stimulation. For IVF it is continued until the day of HCG administration (last dose taken that morning, assuming you have been taking clexane in the morning), and then restarted (often at an increased dose) the day after egg collection (to avoid any extra bleeding making egg recovery more difficult). If you are still bleeding on that day, then its advisable to phone Dr Gorgy (or your consultant) to check. Other clinics will often delay starting clexane until after EC or even until BFP but some clotting issues may have already started to cause a problem by then and clexane cannot dissolve existing clots only prevent future clots. For minor issues, Dr Gorgy may recommend stopping clexane at 12 weeks of pregnancy, but more often he recommends taking it until 31 weeks (by which time the baby is basically viable even if clotting issues start). In cases of significant clotting risk, you will need to discuss it with your Obstetrician as they may recommend continuing it until several weeks after birth.

If your cycle is negative, you should stop clexane as soon as you are absolutely sure there is no chance you are pregnant.

4.3.4 What are the risks/side effects of clexane?Most patients experience bruising at the injection site. There is a small risk of overthinning the blood, so if you experience heavy nosebleeds or get unexplained bruises, you should speak to your consultant or GP. The packet insert suggest you should have your bloodclotting tested regularly whilst you are taking it but most docs seem to say that this is not necessary unless you have symptoms like nosebleeds or bruises. If they are concerned they will run an FBC (to check your platelet count) and/or may arrange a heparin blood test for you (anti Factor Xa test). Clexane can give an increased risk of bone thinning. Most ladies take an over the counter calcium supplement whilst they are on clexane to prevent bone thinning and to ensure enough calcium for pregnancy. . If you need other medical treatment whilst taking clexane, you should mention that you are taking it in case it affects how you need to be treated.

4.3.6 Where should I fill my prescription for clexane?It is worth shopping around for the lowest price. However, if you can satisfy the pharmacist that the clexane is for fertility treatment, ASDA pharmacy may well be cheapest because they currently guarantee to supply fertility drugs at cost price.

4.3.7 Will my GP prescribe clexane for fertility or during pregnancy?This is very much a lottery. If you are having NHS fertility treatment and your NHS clinic prescribes it to you, it should be NHS funded. Otherwise, it very much depends on your GP and your PCT’s rules. Some GPs will not prescribe it at all, some will prescribe it once you have a proven pregnancy (e.g., an ultrasound scan pic). If you have diagnosed clotting issues, you may be able to request a referral to an NHS Haematologist or an Obstetrician who might confirm that you need it and instruct your GP to prescribe it to you on the NHS. Many NHS OBs are happy to prescribe it once you are pregnant as they are more familiar with its importance in preventing blood clots in pregnancy.

4.3.8 How is aspirin taken?Some clinics (Dr Gorgy, AEB) and many non-specialists prescribe low dose aspirin (approx 75mg) for clotting issues including APLAs and to improve bloodflow to the uterine lining. SIRM though are strongly against aspirin as they say that it can cause unpredictable bleeding especially around embryo transfer, and favour more predictable medication like lovenox (clexane). Where aspirin is used, it is usually bought over the counter (its cheaper that way) and is taken daily throughout the whole cycle and the whole of pregnancy, although lately, because there is a lot of controversy over aspirin, and particularly whether or not it helps or hinders implantation, it appears that Dr Gorgy has started to suggest only taking aspirin up until egg collection, but I think the advice may differ where there are additional clotting problems like APLAs where he may suggest resuming taking it from a positive pregnancy test onwards. If you are taking both aspirin and clexane you may want to take clexane in the morning and aspirin later in the day (never take aspirin on an empty stomach).

The cheapest immune protocols used by non-specialist clinics (without any testing) usually use just aspirin and steroids.

A recent study has suggested that taking many kinds of painkillers during pregnancy (particularly between the 4th and 6th month, and particularly where more than one kind of painkiller is taken) might be associated by an increased risk to male babies of undescended testicles (presumably due to interfering with baby's hormone levels) which could lead to reduced male fertility. The painkillers studied included paracetamol, aspirin and ibuprofen.

4.4 Corticosteroids (‘steroids’) – prednisolone, dexamethasone, prednisone4.4.1 What are corticosteroids? What are corticosteroids used for in fertility treatment?The type of corticosteroids used in fertility treatment are taken to suppress the immune system which may help improve the chances of pregnancy and live birth for ladies whose immune system is likely to cause unhelpful inflammation in the uterus or to attack the implanting embryo. As they are inexpensive and low-risk, they are used by many clinics worldwide without full testing for immune issues, but at very different doses.

4.4.2 How do you take corticosteroids? Which corticosteroid is best?The steroids given for fertility treatment are usually tablets which are taken with breakfast. Taking them later in the day will increase the risk of insomnia and taking them without food will increase the risk of nausea. They are commonly started on day 5/6/7 of your cycle/stimulation to ensure they have the chance to dampen your immune system before implantation is expected to happen. Dr Gorgy usually prescribes 25mg of prednisolone (which is equivalent to about 4mg of dexamethasone). Other clinics may prescribe different steroids, starting on different days and in different doses. Some doctors prefer dexamethasone because its longer acting and may give fewer side effects and be easier to taper off but other doctors prefer prednisolone (or prednisone) because it doesn't cross the placenta so is hopefully safer to take a few weeks longer into pregnancy. There are not really any studies comparing the different steroids for fertility purposes but there were a few studies looking specificially at dexamethasone for helping with IVF stimulation (for poor responders and PCOS/PCO ladies) which showed positive results.

You can calculate the equivalent doses of dexamethasone etc using online calculators like this one.

4.4.3 When/how do I stop taking corticosteroids?They are usually continued until about 12 weeks of pregnancy and then tapered off – but your consultant will give you advice specific to your situation. Dexamethasone is sometimes tapered off sooner or swapped for prednisolone because dexamethasone crosses the placenta. If you are healthy (not at increased risk of adrenal insufficiency), haven’t taken them for more than 21 days (or taken them repeatedly for shorter periods), your doctor will normally advise you that its safe to stop them abruptly. Otherwise, they need to be tapered down slowly to avoid your body failing to compensate for their absence by making its own supply of cortisol. This can be very serious, resulting in a life threatening case of adrenal insufficiency (not to be confused with the unpleasant but non-life threatening withdrawal symptoms like headaches and tiredness), so if in doubt, speak to your GP/consultant. Dropping them by half usually doesn’t present any problems but as you reach a lower and lower dose, its sometimes easier on your body to slow the taper – this should avoid you feeling quite so tired and headachy - but unfortunately, most ladies experience some tiredness and headaches and you need to strike a balance in pregnancy between tapering off slowly enough to limit side effects from the withdrawal and doing it so slowly that you (and baby) stay on steroids for longer than necessary because steroids can affect baby's growth and metabolism and your risk of gestational diabetes.

4.4.4 What are the risks/side effects of corticosteroids?The most common side effect is insomnia. The most serious risk would probably be if you caught something like chickenpox whilst you are taking them and didn’t get prompt medical treatment. The longer you take them for, the greater the risk of bone thinning because steroids impair calcium absorption from food (so its advisable to take an over-the-counter calcium supplement for your health and also for your baby's bones - although steroids are normally stopped at about 12 weeks and bone formation takes place mainly later in pregnancy - to get the greatest benefit from your calcium supplements you should avoid taking them at the same time of day as the corticosteroids). There is some risk of increasing any tendencies you already have towards diabetes/insulin resistance (so it may be advisable to ensure you are tested for diabetes in pregnancy as pregnancy will also increase the risk). Some patients experience weight gain, thinning skin and ‘moon face’ but this is not common when they are only taken for a short period of time as in fertility treatment. . You do need to be aware that you might feel extra hungry and be sensible about your eating, but taking it for fertility often overlaps with a few weeks of morning sickness so doesn’t lead to you eating more.

For the unborn baby, there is a small increased risk of birth defects such as cleft lip and cleft palate. Some doctors recommend taking extra folic acid with the aim of reducing any risk.

When you have recently taken steroids and need any other medical treatment, you should mention the steroids to whoever is treating you because it may, for example, affect how they assess your risk for bone fractures, and your NHS OB will want to be aware if you took steroids earlier in pregnancy. Like all other medication, steroids are only supposed to be taken in pregnancy if the benefits outweigh the risks and as they may increase the risk of premature birth, most immune docs will advise you to taper them off as soon as possible in pregnancy (often around 12 weeks) unless you have a medical need to continue them.

Its a good idea to limit your salt and sugar intake whilst taking steroids and try to follow a healthy diet, because steroids will tend to make the body conserve salt and may tend to raise your blood sugar and lipid (fat) levels. Failing to avoid salt and sugar is more likely to give you puffiness and bloating called 'moonface'.

4.4.5 How much do steroids cost?As an example, the cost price of prednisolone is about £1 for 28 5mg tablets and £25 for 56 25mg tablets but the mark-up from different chemists will vary.

For ladies who have not decided to have level 2 immune tests, steroids (together with blood thinners) are often prescribed empirically (see Treating empirically) on a 'just in case' basis after several IVF or pregnancy failures in case there is an undetected immune problem.

In some groups of ladies, treating with steroids and blood thinners, is sufficient to boost the live birth rate almost to a level as high as ladies who have no autoimmune problems, particularly in ladies where ovarian response is good (suggesting that the problem is mainly limited to the implantation environment). However, in cases where autoimmune problems are associated with poor ovarian response, some ladies respond better to treatment than others, so treatment with steroids may help to improve their ovarian response and egg quality, but other ladies find that their ovarian decline may not be fully reversible even after steroid treatment.

This study suggested that the IVF live birth rate might be improved for ladies who tested positive for anti-ovarian antibodies by taking 0.5mg of dexamethasone until their AOA test became negative. Although, they still had a lower live birth rate than ladies who were originally AOA negative.

4.5 Costs4.5.1 How much does immune testing and treatment cost?It will vary enormously depending on what tests you decide to have and what treatments you are advised and decide to have following those tests. I have tried to indicate the costs of most of the tests in the relevant section of this FAQ and also the cost of the medication and how long each is normally taken for. Unforeseen costs can also add up e.g., the cost of extra consults, extra scans and extra drips when there are problems during pregnancy.

4.5.2 Do you have any tips to save on costs?It may work out cheaper to have your drips at Healthcare at Home (or with clinics overseas if that is an option for you, or possibly with another IVF clinic if they will do them, or with a family member if someone in the family is a doctor). However, if you have your drips away from your immune clinic you will be sacrificing having an experienced consultant carrying them out and they will be harder to get at short notice – it may be better to at least have your first drip at your immune clinic.

Don’t buy any expensive supplements until you have checked they are suitable for you, and when you decide what you want, shop around and before buying in bulk consider trying a small bottle first (in case it doesn’t suit you, or it may expire quickly).

Shop around for your medication. This thread may help http://www.fertilityfriends.co.uk/forum/index.php?topic=9821.0Otherwise, Rigcharm pharmacy in Shadwell (London) 020 7790 9150 and Fazeley pharmacy in Tamworth 01827 262 488 may be competitive, but, so long as you can satisfy the pharmacist that your drugs are for fertility, your local ASDA pharmacy (use the store locator function on www.ASDA.co.uk) will often be the cheapest as they have a ‘cost-price’ guarantee for fertility medication. Superdrug have recently announced that they will do ALL private prescriptions for cost-price too.

Do your research on tests in advance so that you can make an informed decision on tests that may be recommended to you. For example, there is little point in paying to have the LAD test done if you are absolutely convinced that you would not want LIT whatever the test shows, or in paying for the greek Chlamydia test if you would not be prepared to take antibiotics to clear Chlamydia if the test comes back positive, or paying for the NK uterine biopsy if you are already going to be taking steroids and Humira, or if you are absolutely convinced that you wouldn’t want to take steroids and Humira and/or IVIG and/or intralipids.

Prepare for your appointments with a questions list and a checklist e.g., for every test recommended you want to ensure that you find out• What its for and why you need it• How much it costs• Exactly what you need to do to get it done• How and when will you get the results

For every medication and treatment you are advised to take make sure you find out and write down• What its for and why you need it• What significant risks there are from taking it• What dose you need• When to start it• When to stop it• How much it costs/whether you can get a prescription to buy it elsewhere • Whether/when you need to book an appointment for it, or obtain a prescription

You may want to ask to have mediation on separate scripts e.g., one script for Humira and intralipids (if you are going to get those from Healthcare at Home) and one script for other drugs like clexane, prednisolone, gestone and any fertility drugs etc so that you can shop around for the cheapest price, or so you can get them from your local pharmacy if that is more convenient for you.

When you get a prescription try to check immediately whether there are enough shots/tablets to last you until you need to revisit your medication (e.g., until just after pregnancy test day, scan day etc), so that if its not enough you can ask for the prescription to be changed.

4.5.3 How do ladies find the money to pay for their Tx plus immunes?I have heard of couples:• Saving up by taking on an extra part time job and cutting expenditure• Selling their house and downsizing/moving in with parents• Remortgaging • Selling cars and other assets• Gifts/loans from family• Taking out loans• Using credit cards – it may be possible to use introductory 0% rates continuously by taking out new cards, but all credit card arrangements can be risky as you may find that 0% rates dry up or your credit status changes and you may find yourself on a very high rate of interest

The only other suggestion I can think of to mention is to try and imagine how you would be forced to cut your expenditure if you and your partner lost your jobs and try to do that now, for example, you might • Forget having holidays away from home and restrict yourself to staying with friends/family• Give up buying discretionary items e.g., cosmetics (if you really had to you could survive with just cheap shampoo, conditioner, deodorant, soap and toothpaste – and just not buy anything else), coffee shops, bought sandwiches, meals and drinks out, alcohol, chocolate and other snacks, gifts, clothes, accessories• Give up gym or any other memberships – you can exercise at home/in the park for free• Plan your shopping and your meals to avoid waste and ‘trade down’ your consumption – swap to value brands for basic items (and trade down retailers – asda really is cheaper than sainsburys for many items), give up ready made food – batch cook something healthy and inexpensive on a weekend (e.g., a turkey leg) ready for meals/sandwiches later in the week and then add fresh vegetables when you serve up (e.g., homemade coleslaw) – give up ‘exotic’/prepared fruit/veg and only buy what is cheap per kg that day (i.e., in season)• Slow down your spending – try not to buy anything on impulse – leave it for now until you are really sure you need it• See if you can cut expenses by switching energy/phone/mobile suppliers, turning down the heating, trying to reduce your travel and phone bills• Look at your spending and see if your ‘treats’ really are benefiting you or whether they are just habits. Once in a while a night out/a takeaway/cinema trip/bottle of wine/posh coffee/concert/theatre is a real treat but if you do it regularly you may not really be getting much cost/benefit from it because you may not really appreciate it and may only be doing it out of habit.

4.5.4 I cannot afford any immune testing or any of these immune treatments. Are there any other possibilities?See Treating Empirically under T, below.

4.5.5 I am pregnant and panicking about the costs of ongoing immunes. How much do I really need to buy for baby? Can I cut costs?

4.6.1 What is the cytokine ratio test? This is a blood test done by various labs in the US including RFU Chicago. It is a measure of the ratio of chemical messengers to each other. TH1 cytokines are associated with the cellular parts of the immune system. TH2 with antibody (humoral) immune activation TH2. RFU measures the cytokines TNFa and IFNg compared to IL10 inside CD3+CD4+ white cells (cells which make a lot of cytokines) in the blood. Higher ratios have been shown to be associated with a lower chance of live birth and are common in many inflammatory conditions (e.g., Crohns, IBS, arthritis, asthma), in cases where there is a DQalpha match and/or elevated NK activity. They may also be elevated under chronic stress or when you have an infection. Beer described the TH1 cytokines as promoting aggression against the body and pregnancy and TH2 cytokines as promoting tolerance against foreign cells (so simplistically he saw high TNFa:IL10 or IFNg:IL10 as unfavourable for fertility and describing a situation which was high in inflammation and usually associated with increased NK cell activity). However, in some autoantibody driven conditions like asthma, dermatitis and rhinitis TH2 cytokines like IL4 and IL13 may be very dominant compared to IFNg (TH1) which can also be described as an inflammatory state, but low TH1:TH2. More recently, there has been a tendency to classify TNFalpha as a TH17 rather than TH1 (although its always classified as pro-inflammatory).

In the RFU and Millenova test, the cytokines are measured in intracellularly (in the cytoplasm of CD4 white cells in the blood). In some of the RIC tests and tests elsewhere, the cytokines are measured in free serum. Intracellular tests require fresh, live white cells (which need to be couriered to the laboratory within 48 hours of blood draw) whereas serum tests can use samples of serum that are centrifuged and preserved so they can be used on samples that are older and have been posted. The different methods of testing at different labs does mean that the normal ranges for tests differ greatly between different labs.

4.6.2 Please explain my cytokine ratio test results?In the RFU tests there will usually be two ratios: TNFalpha to Interleukin 10; and Interferon gamma to Interleukin 10

e.g., TNF-a:IL10 (CD3+CD4+) 38.3 IFN-g:IL10 (CD3+CD4+) 10.9

The TNFalpha ratio is usually seen as more important for fertility and at RFU Chicago anything over 30.6 is elevated. Values over 40 are fairly high. Values over 50 are very high. For tests run at other laboratories, the normal range may be very different. Some labs have started measuring another cytokine, IL17. High IL17 seems to be associated with diminished immunoregulation and may also be proinflammatory.

4.6.3 How is the cytokine ratio test different to a TNFa measurement test?Apparently, TNFa is very difficult to measure accurately, but measuring the ratio of one cytokine to another is supposed to be more accurate. Most immune fertility doctors therefore prefer to use the ratio test rather than the absolute TNFa measurement.

4.6.4 What are the sample requirements for the cytokine ratio test at RFU Chicago?30-40mls of blood collected in green top (lithium heparin additive) tubes – mixed well before posting (tubes rolled end over end about 10 times). Not refrigerated. Must be received by RFU within 48 hours of blood being drawn during working hours. You can have the blood drawn at TDL (on Wimpole St, two doors from Dr Gorgy) or you can arrange to get a post pack from Dr Gorgy/TDL and have the blood drawn at your GP (or local hospital) on Monday/Tuesday afternoon and then post it back to TDL special delivery before 9am so that they add it to their fedex pick up on Tuesday/Wednesday in time to get it to Chicago within 48 hours.

4.6.5 How long does it take to get the results of the cytokine ratio test back?About three days after it is received in Chicago. Dr Gorgy’s patients will need to phone the clinic to ask for a copy of the results (by fax/post).

4.6.6 What are the treatment options for high TNFa ratio?ARGC and Dr Gorgy prefer to use Humira (plus steroids and IVIg and/or intralipids), particularly if the ratio is very high. Dr Sher doesn’t advocate Humira – only steroids and intralipids. In my personal opinion, if elevated TNFa is associated with elevated NK activity, then it seems logical that it may well respond to intralipids as suppressing NK activity seems likely to reduce any associated TNFa. However, if TNFa is elevated in the absence of elevated NKa, it is not obvious how intralipids would help, whereas Humira is specifically targeted at blocking TNFa. However, success rates at clinics that don't use humira are often very good, so for some ladies the combination of steroids plus intralipids without Humira clearly does work. Other options like resveratrol, fish body oil or pre-treatment with low dose steroids also seem to work.

5.1 Deciding to see a reproductive immune specialist5.1.1 What are the most common reasons for deciding to have immune testing/see a reproductive immune specialist?I think they are often:

• repeat miscarriage/early pg loss/chemical pgs – could be due to many explainable reasons that a reproductive immunologist can help pinpoint and treat • late miscarriage/stillbirth - of a karyotype normal fetus without any physical explanation – could be due to many explainable reasons that a reproductive immunologist can help pinpoint and treat • repeat IVF failure – could be due to many explainable reasons that a reproductive immunologist can help pinpoint and treat • history of autoimmune disease in you or your genetic family - e.g., rheumatoid athritis, Crohn's, coeliac, ulcerative colitis, multiple sclerosis, sarcoidosis, diabetes, lupus, thryoid disease (e.g., Hashimoto's - Dr Sher estimates that 50% of ladies with Hashimoto's have severely elevated natural killer cell activity), fibromyalgia, CFS, endometriosis (some docs believe this has an autoimmune cause) – increases the risk that you will have autoimmune reasons for not getting/staying pregnant e.g., high TNFa• history of endometriosis - Dr Sher estimates that about 30% of ladies who have any degree of endometriosis also suffer from severely elevated natural killer cell activity• abnormalities in 'level 1' tests e.g., elevated ANAs, antiphospholipid antibodies, other clotting issues, thryoid problems, insulin resistance – increases the risk that you will have autoimmune reasons for not getting/staying pregnant e.g., high TNFa and/or need specialist advise on how best to treat the issues already identified for fertility (sometimes something sub-clinical (not causing you a significant health issue and therefore not regarded as problem for your health by your GP, could still be causing a fertility problem)• always feeling ill at implantation time e.g., flu/fever/joint pain – this could indicate a DQa match or something else that causes immune ‘flare’ on implantation e.g., uterine infection• history of anxiety/depression – can be associated with other hormonal (or autoimmune) issues and sometimes with elevated TNFa• infection history e.g., Chlamydia, chickenpox – can be associated with immune ‘flares’ or even triggering autoimmune disorders if you have a genetic susceptibility• secondary infertility which isn't explained by male factor or other 'new' issues – may indicate that a DQa matched earlier pregnancy has triggered problems • gut feeling that something is wrong • emotional reasons - feeling that you cannot keep trying without being sure there is nothing wrong or worrying that you don't have time to try before ruling out these issues, or cannot afford financially/practically to try many more times without more information, or being the sort of person who needs to feel they have done everything possible and wants to ‘take charge’ of their treatment.

5.2 Diet5.2.1 Is there anything I should eat or avoid eating to help my immune issues?Generally, you are best avoiding anything which you know upsets your digestion. So if white bread or dairy food makes you bloated, I would say to avoid it because any inflammation of the gut may increase your TNFa. Some ladies find a gluten free (or even a dairy free) diet helps if they have that sensitivity. Some ladies with digestive issues recommend a supplement called wobenzyme (but I haven’t used it). There is a section on other supplements below.

A diet high in saturated fats and low in unsaturated fats will tend to increase NK activity and TNFalpha (and vice versa – which is basically the mechanism that intralipids are supposed to work by), so to minimise those problems its best to avoid foods high in saturated fats (pastry, cakes, biscuits, sausages, butter, chocolate etc). 'Good' unsaturated fats include the monounsaturated fats like olive, avocado, rapeseed/canola, and the polyunsaturated like fish oil, hemp and walnut. For men, high consumption of saturated and monosaturated fats compared to polyunsaturated fats has been linked with lower sperm counts. In women, high consumption of polyunsaturates like sunflower and saturates like butter compared to monounsaturates like avocado and olive has been linked to lower egg numbers in IVF cycles.

Some ladies decide to try to eat organic food in order to reduce their exposure to pesticides etc. I am not convinced that the expense is worthwhile, but it can't do any harm. However, it makes sense to me to try to limit your pesticide exposure cheaply by avoiding eating a lot of food from one source e.g,. if you are buying, say, juice, you might want to alternate different brands so that in the event that one brand is particularly high in pesticide residues, at least you are not being exposed to as much of it as you would be if you used that brand all the time.

I think its also worthwhile avoiding using non-stick pans and cookware (and trying to avoid buying new 'scotchguard'ed furniture/carpets etc when you are trying to conceive) because the solvents used to make PTFE have been shown to be associated with reduced fertility (although good quality, undamaged cookware is unlikely to contain much volatile solvent) . Stainless steel or 'black iron' is probably the safest material for pans.

Mercury in the body has also been shown to be associated with reduced fertility. One source of mercury would presumably be amalgum from silver coloured fillings - however, removing amalgum will in itself risk additional mercury ingestion - so its not obviously a good idea to decide to have amalgum fillings replaced when you are trying to conceive - but you might want to decide to have any new fillings done in mercury free materials. A more likely source of mercury contamination is probably fish intake, so it makes sense to limit consumption of fish like tuna and swordfish (fish that are long lived and at the top of the food chain) as they are more likely to contain significant levels of mercury. Fish like 'ordinary' mackerel (not King mackerel), squid, cod etc are unlikely to contain a lot of mercury.

You may also want to avoid using shampoos, conditioners, cosmetics etc containing the 'gender-bending' chemicals pthalates and parabens as these have been linked to reduced fertility. For the sake of baby's health, you will probably want to avoid toothpastes containing the very commmon ingredient, triclosan, which recent studies have suggested are linked to reduced blood flow to baby. When you are pregnant or during the two week wait, you will probably want to avoid alcohol, foods with a high risk of listeria (pate, unpasteurised cheese etc), and should avoid contact with cat faeces (risk of toxoplasmosis).

I also try to avoid caffeine entirely as it is supposed to reduce bloodflow to the uterine artery (which is unhelpful for lining growth or ovarian response). Very high caffeine consumption has been linked with increased risk of miscarriage and also with reduced efficiency of the fallopian tubes.

5.3 DQ Alpha Genotype (DQa) test5.3.1 What is the HLA-DQa test?The surface of our cells are covered in proteins which are used to communicate with other cells in the body. Patterns of proteins are called ‘markers’ and the DQalpha (DQa or DQA1) marker is one of these. Everyone has two DQa markers (which are expressed on most of their body cells). One is always derived from your mother and one from your father. So any embryos produced from your eggs will have one of your DQa markers and one from your partner/sperm donor. You are born with your markers and they never change. Consequently, you will never need to have your DQa markers retested.

5.3.2 How much does the DQa test cost?The cost of DQa testing with Dr Gorgy is approximately £210 (including both partners).

The cost of DQa testing with Care is approximately £290 (including both partners).

Its about 80Eu person with Dr Economou in Athens (see my thread about serum clinic)

5.3.3 How do I understand my DQa results?

Step 1: translate the DQa numbers into allele numbers using this list from pg 302 of Dr Beer’s book (we do this because the body tends to treat markers on the same allele as being almost identical):

Step 2: work out what embryo combinations you can make with your allele numbers and your partner’s allele numbers – drawing a three x three box grid might help but basically you need to work out the four different combinations you can make if you take each of your two numbers and combine it with each of his, like this (by convention, the lower number is always written first):

Step 3: how many combinations match your numbers exactly? In this example, the mother is (2.1, 4.1) and because the father has (2.1, something), there is only 1 combination which matches the mother.

The theory is that if the embryo is an exact match for the host mother (regardless whether own egg or donor egg), it is more likely to be seen as ‘altered self’ and trigger an unhelpful over-aggressive immune response. If you have one possible match in four, that means that, on average, for every four good embryos you make as a couple, one of them (25%) will match you and be at increased risk of triggering an immune response. If you have two matches in four, the risk will be 50%. If you have four embryo matches in four, all your embryos could trigger an immune response (100%), if your body fails recognise the embryo as ‘foreign’ and ‘benign’ rather than ‘altered self’.

Examples:If you work out the 4x4 grid for this combination, it will give you 1 match (25%)(1.1, 2.1)husband, (1.1, 3.1)wife

The grid for this will give you 2 matches (50%)(1.1,2.1)husband, (1.1,2.1)wife

The grid for this will give you 4 matches (100%)(1.1,1.1)husband, (1.1,1.1)wife

A matched embryo will not necessarily always trigger an aggressive response, but the theory is that it is more likely to, if the mother’s body fails to distinguish it properly from ‘self’.

5.3.4 If I have DQa matches, what can I do?There isn’t one answer to this, but possible strategies are:1) Do nothing new and hope it is not a problem/does not become a problem due to increasing sensitisation - for example, according to Dr Sher, exposure to DQa matched embryos, for some ladies, will result in immune sensitisation leading to raised NK killing power, but until this happens (i.e., until your NK assay becomes high), your chances of live birth are not affected. If your NK killing power is raised in the presence of a DQa match, he suggests it may be treatable given closely spaced (e.g., 2 weekly) intralipid drips provided your immune system responds well to the drips.2) Consider having LIT (see below) – in theory, the better you can get your body to recognise paternal DNA as ‘foreign’ and not ‘self’, the lower the risk of raising an unhelpful immune response.3) Consider transferring embryos one at a time – theoretically, this should avoid the risk that an unmatched embryo is attacked purely because its transferred at the same time as a matched one – however, if you have two embryos available to you, you need to think about whether the remaining embryo would meet criteria for freezing (and the likelihood it would survive the thaw), and if you are older and/or have poorer quality embryos you might question whether there is that much of a chance that both embryos have the genetic potential to try to implant.4) Consider more aggressive immune treatment to deal with the consequences of having a matched embryo e.g., pre-conception treatment with Humira, pre and post-conception treatment with IVIG/intralipids/steroids etc.5) Consider the protocol used by SIRM (and Care) – corticosteroids with intralpids pre conception then repeated every 2 weeks until about 22 weeks of pregnancy6) Consider monitoring NK levels in pregnancy so that you can have extra IVIG/intralipids if your immune system flares due to matching.7) Consider surrogacy, or possibly donor sperm – presumably as a last resort if all other measures fail.

5.3.5 Why do people worry about having a (4.1, 4.1) embryo?Dr Beer had a theory that embryos which were (4.1, 4.1) would usually be aggressively attacked by the immune system regardless of whether they were a match for the host mother or not – but this theory hasn’t been scientifically proved. Additionally, if it was an insurmountable problem, it is hard to understand why there are so many of us in countries like the UK who are allele (4.1, 4.1). The most common allele number in the UK and many other ‘western’ countries is 4.1. We were all embryos once and we survived (presumably without our mothers having steroids, IVIG or LIT etc), so I would be more optimistic than Dr Beer’s book suggests. That said, Dr Tsagaris (in Athens) does seem to regard 4.1 matches as more serious than other matches as he adheres to Dr Beer’s theories.

5.3.6 Should I have the DQa test?Dr Gorgy, Dr Nduwke and Dr Sher recommend this test, as their understanding is that if you have DQa matches it may explain your immune responses and it may indicate to them how intensive your immune treatment may need to be, and in severe cases (where there is a DQa match that seems to be causing very high NKa), Dr Sher suggests that it may indicate that you may never achieve your own pregnancy with your own partner, but other doctors are more optimistic, particularly as there may be other causes for elevated NKa that may respond to treatment. (Dr Sher seems quicker to suggest surrogacy rather than more aggressive immune treatments than other doctors, and I wonder whether this is because surrogacy is easier to arrange in the US than it is in the UK. ) I believe that AEB have stopped relying on this test as they rely more on testing and treating the consequences as they arise. I am not sure whether ARGC ever recommend this test.

If you are using donor eggs, the DQa test is probably still relevant as the match between the host mother and the father of the embryos is still important. The egg donor will contribute 1 of the DQa matches, which may help to reduce the chances that the embryo is a match for you, but its still a possibility depending on your partner's DQa and the egg donor. Another key reason to have the DQa tests done even if you are going to have donor egg/embryo etc is in the situation where you have raised NKa (and possibly TNFa), as you will want to know if a history of DQa matches may have caused your NKa problem. The reason you would want to know if a match has caused the issue or may still cause an issue for you is that, according to Dr Sher etc, if raised NKa is caused by a history to DQa matches it is more difficult to treat and requires more/more frequent doses of immune modifying drugs (e.g., intralipids).

If you are using donor sperm&donor egg/donor embryo then I think you should discuss whether the test is going to be relevant in your circumstances, but if you are going to be considering LIT, then knowing your DQas would be helpful, but you could think about testing LAD first and then only having the DQa test if your LAD is low (although this would add to the timescale).

5.3.7 How long do DQa results take to come back?At least one week after they arrive at RFU but sometimes up to three weeks.

5.3.8 What are the sample requirements for the DQa test at RFU ?20-30mls of blood collected in lavender top (EDTA additive) tubes – mixed well before posting (tubes rolled end over end about 10 times). Not refrigerated/frozen. You can have the blood drawn at TDL (on Wimpole St, two doors from Dr Gorgy). You can arrange to get a post pack from Dr Gorgy/TDL and have the blood drawn at your GP (or local hospital) on Monday/Tuesday afternoon and then post it back to TDL special delivery before 9am so that they add it to their fedex pick up on Tuesday/Wednesday in time to get it to Chicago within 48 hours. However, I believe as the sample does not depend on the cells being alive, the duration of transit time to Chicago should be less critical than for other Chicago tests.

Some studies have suggested that cutting/scratching the uterine lining in the cycle before IVF/FET may improve implantation rates and live birth rate. The theory is that causing minor damage to the lining can alter the expression of various proteins which are helpful for allowing implantation. For example:

This technique is gaining acceptance e.g., its offered by Lister, Guys, Gorgy etc and appears to be very much favoured by Serum (although they use a deeper cut rather than a scratch).

In terms of timing, most docs seem to favour doing the scratch in the previous cycle (i.e., scratching the lining before it is shed immediately before you start taking estrogen or stimulation drugs to build it up again) e.g., roughly around day 21 of the previous cycle. Studies have suggested that doing the scratch very close to embryo transfer, e.g., on egg collection day, is too close as it reduces pregnancy rates, but doing the scratch at the beginning of the same cycle (about 2 weeks before ET) seems to be ok, as does doing the scratch in the previous cycle.

If the scratch cannot be done ahead of time, it may be possible to do a saline wash or aquascan a few days before ET because that is less destructive to the lining, but should still get some of the same benefit by generating very minor, local injury to the lining.

6.2 Endometriosis/Adenomyosis Endometriosis is a condition where uterine lining tissue starts to grow outside the uterus e.g,. on the tubes, on the ovaries, on the bowel and on other structures in the abdominal cavity. It is hard to diagnose - and can only be confirmed by laproscopy - inserting a fibre optic camera through a keyhole cut in the abdomen to look inside. It is usually only investigated for if a patient has symptoms such as severe cyclical pain, but it is possible for it to be pain-free and only be discovered when a laproscopy is performed for another reason. Having endometriosis appears to be strongly associated with another condition called adenomyosis which affects the uterus and causes a thickening of the uterine walls and poor blood flow to the lining but is also very hard to diagnose.

Adenomyosis can really only be confirmed with 100% certain by removing a sample of tissue from the uterus or dissecting the uterus after hystorectomy (surgical removal of the uterus), but a skilled doctor can often detect signs of adenomyosis as an uneven look to the uterine tissue on ultrasound - either a hyperplasia (thickening) of the inner myometrium or a heterogeneity (uneven look on ultrasound) of the inner myometrium.

Endometriosis and adenomyosis are risk factors for infertility and in particular appear to be risk factors for having immune fertility issues such as raised NK killing power and elevated inflammatory cytokines. So most immune fertility doctors will immediately suggest tests for NK activity and TH1:TH2 cytokines where they suspect endometriosis or adenomyosis.

Basic immune treatments for ladies with endometriosis (and adenomyosis) are the same as for other patients (intralipids, steroids and possibly humira). However, also bear in mind:

1) a fresh removal of endometriosis by laproscopy (excision/laser) may help to reduce inflammation - however, for mild/moderate symptom-free endometriosis a lap may be unnecessary and even do more harm than good by causing scarring or reducing ovarian reserve. Even for severe endometriosis, several studies haven't shown any increase in IVF success rate after surgery - although some docs think that laser removal for severe endometriosis may be very helpful.2) vitamin D deficiency may increase inflammation (see supplements, vitamin D) and exacerbate endometriosis so it may be worth getting your blood level tested and addressing it with supplements (plus eating oily fish e.g., mackerel and walking outside every day, but high levels of vitamin D may exacerbate endometriosis too.3) an extended down regulation on agonist e.g, prostap for at least 3 months (maybe 6 months) may help to reduce endometriosis/adenomyosis by starving it of estrogen (one study showed a 4 fold increase in pregnancy rate http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004635.pub2/pdf/standard)

(but may cause problems with ovarian response in ladies who are prone to poor response - although are ideal for ladies doing FET or donor egg)4) a resting month or more on a low dose pill may help calm endometriosis/adenomyosis somewhat before treatment but may not suppress the endometriosis quite as much as agonist - the pill is less likely to cause problems with poor ovarian response for OE but some ladies may still struggle to recover their normal ovarian response after a month on the pill, so might want to investigate an overlap of the last 5 days of the pill with agonist to cause a mini FSH flare before starting stimulation and switching to antagonist (conversion protocol - see IVF)5) high doses of stimulation leading to high levels of estrogen, may make endometriosis and adenomyosis worse because estrogen 'fuels' endometriosis - so older ladies/poor responders with endometriosis/adenomyosis may be better off with a natural cycle (no stimms) IVF - see IVF6) recent studies have suggested that treatment with letrozole/femara may help some ladies with mild/moderate (and even undiagnosed mild) endometriosis - either during an own egg IVF or during a DE or FET cycle, as there seems to be a high risk that mild/moderate endometriosis or adenomyosis sufferers lack a crucial cytokine in their lining (called beta3 integrin due to over-expression of aromatase - the same lack of beta3 integrin appears to occur with large hydrosalpinges). Letrozole is an aromatase inhibitor which was shown to improve the pregnancy rate in this small study and also to correct the beta3integrin deficiency for most of the patients it was tested on.

The protocol used in this OE study was a long protocol (down reg with agonist) with stimulation beginning on day 3 of the bleed and 5mg letrozole being used on days 2-6. The authors felt that the letrozole helped to reduce the risk of poor response as well as correcting the beta3integrin deficiency. The letrozole therapy is likely to be more effective if the endometriosis is suppressed first before the cycle by laproscopic laser removal (particularly if it is moderate rather than mild) and/or a very long down reg (e.g., 6 months) or at least one 'resting' cycle on a low dose pill.

There is no reason why a similar protocol (e.g,. 5 days of 5mg letrozole started on day 2 of estrogen) could not be used with donor egg or FET, although it would need to be a medicated transfer (using estrogen tablets/patches etc) rather than a natural transfer because, used without the pill, agonist or estrogen, letrozole is an ovarian stimulant (it is sometimes used as an alternative to clomid). At least one resting cycle before the treatment cycle should be helpful - either on the pill, or preferably on down regulation.

The proponents of letrozole for endometriosis (Lessey etc) seem to think that it may be helpful for use more widely for ladies with implantation failure - not just ladies diagnosed with endometriosis/adenomyosis/hydrosalpinx - because they think that mild endometriosis with implantation failure is probably under-diagnosed (ladies with no symptoms of endometriosis are less likely to have a lap and therefore less likely to know that they have endometriosis).

Dr Braverman in the USA has also started using letrozole with his repeat implantation failure with reportedly good initial results.

6.3 Exercise6.3.1 Should I exercise as normal during my immune fertility cycle?In my opinion, you should try to moderate your exercise programme. Your body cannot invest as much in reproduction if it is working at full capacity on demanding activities. Pregnancy rates in the ‘normal’ population have shown to be lower in heavy exercisers for this reason, and I feel that ladies with immune issues need all the help they can get. Additionally, if you are undergoing an IVF cycle, there is a risk of torsioning of the ovaries if abdominal activity is too severe as the ovaries may be swollen. Heavy exercise is also likely to increase your risk of dehydration which will be unhelpful as it will increase the tendency of the uterus to cramp. Heavy exercise may also increase your immune activity. Gentle exercise like walking is probably going to be beneficial though and can help relieve stress. Personally I would avoid swimming due to the slight extra risk of infection which might be more of an issue for an immune Tx lady.

6.3.2 Should I exercise as normal during my pregnancy?In my opinion, if you have immune issues, you need as little stress on your body as possible, so should stick to gentle exercise and avoid swimming at least in early pregnancy. Many immune Tx ladies will be assessed as high risk in pregnancy – as they may be over 35, have other health issues, be carrying twins, have experienced bleeding in pregnancy etc – and they may be advised by their doctor to be more careful about limiting their activities in pregnancy – so you should check with your consultant and not assume that your normal activities are safe.

7.2 Fears about immune treatment7.2.1 I am worried about taking immune drugs (prednisolone, clexane, Humira, intralipids, IVIg)I think everyone worries when they take a drug for the first time and don’t know what to expect. I would suggest talking to your consultant about any specific worries you have. When reading patient information leaflets or getting information from your pharmacist, the side effects and risks can sound very frightening. It may help to look at the package insert on a box of paracetamol or other drugs you are happy to take just to get a sense of perspective as medications that we take all the time have rare but worrying side effects too, but we forget this because we are used to them. Talking to other patients/ex-patients about their experiences may also help you feel reassured. Also bear in mind that these drugs may be relatively rare in fertility/pregnancy use, but are much more common around the world for other purposes e.g., steroids are taking routinely by hundreds of thousands of patients per year for all sorts of common medical ailments, blood thinners are also taken very widely, Humira is taken by increasing numbers of rheumatoid arthritis/Crohn’s/ulcerative colitis patients, intralipids are taken widely by patients who need intravenous nutrition (patients who are unable to eat food) and IVIG is prescribed for many different conditions including severe immunosuppression that occurs with e.g., with cancer treatment. All these drugs are primarily manufactured to save lives/reduce pain – any fertility benefits are basically just a side effect.

7.2.2 I am worried about giving myself injectionsFor some of us, this turns out to be something that we deal with a lot better than we expect i.e., we anticipate it being very unpleasant and then find out its not so bad when we do it, and eventually it becomes so routine that we are not bothered. You can find videos of other ladies dealing with their subcutaneous injections (e.g., gonal F, menopur) or their intramuscular injections (e.g., gestone) on the web, e.g., youtube. To deal with anticipatory fears, you might want to see if a doctor or nurse can do your first injection for you, or see if your friend/partner will do the injections for you routinely if that will help you. You may find talking to someone who has taken the same medication may help as they may have tips on how to do it and give you more confidence about how simple it is. To deal with serious phobia, you might want to see a professional before you start your treatment e.g., a psychotherapist or maybe a hypnotherapist.

7.2.3 I am worried because I am getting different advice from different doctors This is extremely common, particularly with immune Tx, but also with fertility treatment generally. Many doctors express their opinions forcibly, even when they have little knowledge of a particular area – after all they are used to having to be authoratitive in their day to day work so that their patients can feel reassured by their apparent expertise. Even in mainstream fertility treatment there can be huge differences in opinion on fairly simple questions e.g, whether gonal F is superior to menopur or not, or how long progesterone support is needed for and at what dose. Immune treatment is even more specialised and controversial because the patient studies that are available are so small and not widely known or understood. So I try to keep in mind that, given the state of our medical knowledge at the moment, no single doctor has a monopoly on being right or knowing all the answers, and so long as you are logical in your own thoughts, then if you have a choice between following the advice of one doctor or another, going with your gut instinct is often the right decision, and if you are wrong, usually you can decide to try the other route later on if your first choice doesn’t pan out.

7.2.4 I am worried because I forgot to take my medication on time or that I don’t understand the instructionsYou can always call your clinic – although there may be a charge depending on what arrangement you have with them. Alternatively, your GP might be able to help. Other ladies who have had the same treatment might be able to reassure you, but your consultant is the best person to give the right advice. There are very few situations where missing a day’s worth of medication or taking it later is going to be critical - except maybe your HCG trigger shot - but even that situation can probably be rescued.

7.2.5 I am worried that my cycle won’t work because I am stressed, or that my treatment has not gone as smoothly as I was expectingIts true that patients who suffer from long term stresses or anxieties are more likely to have autoimmune problems (e.g., high TNFa)– however its not a certainty, and both short and long term stresses may affect different people differently - after all, some people really do thrive on certain kinds of pressure. In addition, I can think of many people who were going through a terrible time stress-wise on the cycle that they eventually managed to conceive. I can also think of many people who had their worst egg recovery rate, worst fertilisation rate, worst quality embryos, were feeling really poorly or had a difficult embryo transfer – but still got pregnant on that cycle. If you are feeling stressed and pessimistic about your treatment at the moment, the best thing you can do to improve your chances is to try and find a practical way of reducing some of the effects on you – even if you can’t change the life situation causing them. You may not be able to afford to give up your stressful job today, but maybe you could have a week off, or if its during your Tx, see if your GP agrees that you need to be signed off for a week, or just get out for a walk, or throw away that chocolate bar and have an apple instead, or go see a friend to get things off your chest. If you do one thing that is within your control, no matter how small, it might make you feel better straight away.

G-CSF (granulocyte colony stimulating factor) is a natural cytokine (chemical messenger) which is normally found in the body, and neupogen (filgrastim) is a synthetic (recombinant) form of G-CSF . Higher levels of natural G-CSF seem to be found in follicles which go on to produce healthy eggs compared to follicles which produce poor eggs. Higher levels of G-CSF are expressed in healthy embryos and in healthy placenta, so it is a marker of embryonic/placental viability that seems to have a role in communicating with the endometrium to allow implantation. Dr Braverman who is promoting it in the US http://www.reproductiveimmunology.com/amazing-new-treatment-for-recurrent-misciarrages-and-failed-ivf-neupogenc-gsf/ seems to be suggesting that it may improve lining thickness and egg quality (although the number of patients he has tried it out on for egg quality is apparently very small), as well as placental growth and may permit a successful live birth for ladies who have failed to respond to IVIG. For patients who respond well to it, he believes it can replace IVIG.

Neupogen is licenced in the UK to treat severe neutropenia (low neutrophil (a type of white blood cell) count). Studies on giving GCSF to pregnant animals showed some problems so pregnant women taking the drug for neutropenia were initally advised to stop it, but then studies showed that pregnancy outcomes (for mother and baby) were much better for neutropenic patients who remained on the drug, so I think patients taking it are now advised to stay on the drug (http://www.hemonctoday.com/article.aspx?rid=78330).

Two significant studies have been performed by doctors in Rome and Munich.

http://www.medscape.com/viewarticle/712831 Scarpellini et al 2009 - (you may have to register for medscape to read the article). In the Rome study, unexplained repeat miscarriage patients who were trying to conceive naturally were given 1mcg (100 000 IU) per kg of their body weight per day (e.g., for a 70kg lady, 70mcg or 7 million units - at about £65 for 300mcg, this works out about £15/day) of GCSF from 6 days post ovulation until the onset of the period (if unsuccessful) or until 9 weeks of pregnancy (so about £660 in total, or £165 if cycle is negative). The live birth rate was 83% compared to the control group's live birth rate of 49%

In the Munich study, 13 million units (130mcg) of G-CSF was administered every 3 days from egg collection onwards in fresh IVF patients who were shown to have a genetic defect (absence of 3 killer cell-like immunoglobulin activator receptors) after 5 or more failed IVF cycles or several years of unexplained infertility. This study showed a very high pregnancy rate 74% but also a high miscarriage rate (38%) - although potentially that might have been because the G-CSF therapy was stopped on test day? However, although the incidence of the KIR defect (3 missing activators) was very high, (78% of the patient group who had 5 or more failed IVF or an average duration of unexplained infertility of 6.8 years - this compares to about 30% of the typical population), when the same G-CSF therapy was used with patients who did not have the KIR defect, the pregnancy rate was much lower (only 10%). This suggests that although about 3/4s of patients with 5 or more failed IVFs or long term unexplained infertility may benefit from G-CSF due to the faulty gene, the other 1/4 may get no benefit from G-CSF. In other studies (http://humrep.oxfordjournals.org/content/23/4/972.full), the KIR defects were found in 28% of the caucasian population but 41% of repeat miscarriage patients. At £65 for 300mcg, this would cost about £135, but I would guess the miscarriage rate might be reduced if it was continued until 9 weeks of pregnancy (at a cost of another £270).

The munich doctors have previously (2000,2003) published studies showing an improved pregnancy rate (43% compared to 20%) where 300mcg of molgramostin (GM-CSF) was given as a single dose injection on the day of ET, but I haven't been able to get a free copy of the full journal articles. I assume though, that given that they have moved on to using neupogen in continuous therapy (i.e., regular doses), that it must be a superior treatment?

I found a number of studies on GM-CSF (granulocyte macrofage colony stimulating factor) expression (as well as G-CSF) expression and lab and animal studies, but apart from the study with molgramostim, and some information about adding GM-CSF to the culture medium used in the embryology laboratory for growing IVF embryos which suggested that a new culture medium improved the implantation rate at also the live birth rate (by 28%) in ladies who had suffered repeat miscarriages following IVF. A commercial culture medium (called EmbryoGen manufactured by a Norwegian company called Origio) containing GM-CSF has been developed by scientists in Australia (including Dr Sarah Robertson) and Norway and is now licensed in the EU and is due to be available shortly. The theory behind this is that embryos that are more successful at implantation have higher natural levels of GM-CSF which may help to switch off some of the stress markers in the embryo and it appears it may be possible to increase the level of GM-CSF by adding it to the medium that the embryos are incubated in: http://www.origio.com/~/media/6679ECD7069A4E2292675746F05AA869.ashxOther studies suggest that it can't improve the genetics of the embryos, but perhaps by reducing markers of stress and improving signals favourable to implantation, it somehow promotes implantation and better growth of the trophoblast. I don't know which clinics are using it in their culture medium.

GM-CSF as molgramistin and leukine was developed as a treatment for leukaemia and multiple sclerosis but doesn't appear to be a licenced drug in the UK (except for the EmbryoGen culture medium).

A very small study used a single, slow, intrauterine infusion (using an ultrasound guided catheter attached to a syringe) of 300mcg G-CSF as 'rescue therapy' for 4 ladies who had thin lining. All 4 ladies managed to reach at least 7mm lining thickness 48 hours after the infusion which was performed between 2-9 days before ET. In one case, the lady presented with an accumulation of fluid in the uterus which was aspirated out first before G-CSF and did not recurr after the infusion.

A published case study http://www.freepatentsonline.com/y2010/0080837.html for a lady who had 6 first trimester miscarriages following successful pregnancies used a regime of 100mcg (10m units) of G-CSF from positive pregnancy test for 30 days. Another published study of an IVF pregnancy used 100mcg of G-CSF daily from 7 days before FET (or from egg collection) to 30 days after (so until about 6 weeks of pregnancy). At £65/300mcg, this would cost about £800.

I am not aware of any doctors offering it widely in the UK as yet - although apparently Dr Gorgy is prepared to prescribe to patients who are cycling with him and who ask for it, or whether it is likely to be a better or worse option than intralpids (or ivig) for ladies who respond to those. It does seem to be cheaper than IVIG (something like £5-20 per day up to 9 weeks of pregnancy). It has some serious potential side effects but they seem to be fairly rare and in the small pregnancy studies done so far, there were no increases in birth defect rates. The side effects in neutropenia patients are worth bearing in mind though (although the doses used in neutropenia tend to be a lot higher than for fertility):Nausea (57%)Vomiting (57%)Bone pain (22%-33%)Alopecia (18%)(hair loss)Diarrhea (14%)Fever (12%)Fatigue (11%)

My initial view is that it sounds promising but I don't know enough about it and as far as I can tell there haven't been any studies on using it for ladies who might otherwise respond to intralipids. It is probably likely to work better for younger women who have excellent embryos/women using donor eggs (without significant sperm problems) but who have a implantation problems, rather than women who are struggling with repeat miscarriage/implantation problems due to poor eggs (or sperm).

There is a research trial currently in progress to test for any enhancement in inplantation/pregnancy rate. The protocol is:two intrauterine infusions of 300mcg G-CSF 48 hours apart before embryo transferhttp://clinicaltrials.gov/ct2/show/NCT01202656

The main effect of injected GCSF is to increase the white blood cell count - but the NK cells tend to be immature and not programmed to be very cytotoxic which helps to increase the immune system's tolerance for the implanting embryo. Before you start GCSF it is helpful to have a baseline FBC so you can know what sort of WBC is normal for you. Then you would have a repeat FBC after starting treatment (after 1-2 weeks) to check that your WBC is rising but is not too high. Levels over 40,000 (about 4 times normal) start to be a concern, but some women have apparently had levels more than double this without a problem. If there is any tenderness around the spleen (left upper belly - or pain referred to the shoulder tip) at any point, you would need to see a doctor urgently as there is a risk of rupture of the spleen if levels go too high. Similarly if you have a rash, difficulty breathing or other signs of allergic reaction you need to speak to a doctor.

I don't know of anyone offering it, but it would seem to me that a logical approach to consider might be to try 300mcg by slow intrauterine infusion on around 3-7 days before ET (mainly if you have thin lining problems), followed up with either daily injections of 1-1.5 mcg/kg starting 2 days later until 9-12 weeks or injections of 2-3 mcg/kg every 2-3 days until 9-12 weeks. However, I spoke to Dr Braverman about doing this and he felt that unless there was a lining problem, it might make more sense (on a DE cycle) to start 100mcg injections at least 7 days before ET and continue on them until 9-12 weeks of pregnancy as he felt that the only proven effect of infusions is to improve lining thickness, so if lining thickness is not a problem, then shots MAY be more helpful as they have a systemic effect. Some experimental trials done where GCSF infusions were given just before transfer did not appear to show favorable results.

8.1.2 Practical points about G-CSF therapy

According to BNF.org, neupogen in the UK should be available in 300mcg vials (1ml), 300mcg prefilled syringes (0.5ml) and 480mcg prefilled syringes (0.5ml). When I checked the prices for 5 syringes/vials of 300mcg neupogen were:

Asda £316Central homecare £363Superdrug £266

However, Asda was not sure when they will be able to get the vials rather than the pre-filled syringes, and if you are wanting a dose less than 300mcg, it may be more awkward to split the dose in a pre-filled syringe than a vial. Central homecare and superdrug both said they could supply the vials, so on that basis, I would opt for Superdrug as its significantly cheaper.

Neupogen needs to be kept in the fridge (2-8deg C) but brought to room temperature just before injection (so you would need a coolbag, bubble wrap (to stop it freezing) and icepacks to transport it). Once it has been out of the fridge for more than 24 hours the manufacturers say it should be discarded.

It seems logical that you ought to have regular FBC tests to make sure you aren't at risk of a damaged spleen (from too high a white cell count). Presumably the initial tests need to be closely spaced but then could be done monthly if everything is going well for you. Clearly a doctor has to be in charge of deciding when you need to be monitored and what the test results mean for you.

There is a concern that taking steroids on top of GCSF may not be helpful, so it is logical that unless you have very high TH1 cytokines, you would expect your doc to start you on GCSF injections first, then check your TH1:TH2 after a few days before deciding whether to start you on steroids - in case you have a reaction to the GCSF that pushes up your TH1 (so you want steroids) or pushes it down (so you want to avoid steroids).

The vials are currently hard to get hold of, so that only the singljects may be available, and additionally when you are trying to inject tiny doses it can be tricky to get it right. So currently, some clinics are suggesting to inject the dose into a new vial (supplied by them) and then use an insulin syringe to get the right dose, or to inject the singleject into a used P pen cartridge, then use a P pen to dial up the dose that you need (with a fresh needle each time).

8.1.3 Should I test for the KIR activator defectsThe rate of this defect is very high - 30% of the population, and seems to be even higher in patients who have many years of repeat implantation failure (78% in one study). So, if you are someone who has had many years of repeat implantation failure it is more likely than not that you will test negative for all 3 KIR activators. If you are in Athens anyway, then you might want to do the test, or if you are considering trying GCSF you might want to do the test, given that GCSF seemed (in one study) to reduce the pregancy rate for women who weren't missing all 3 activators. If you fit the profile of many years of implantation failure and its going to cost you a lot to make a separate trip to athens or send bloods by special courier, then there is an argument for just trying GCSF injections and not having the test done.

8.1.4 What does my KIR result mean?My understanding is that their are two haplotypes for KIR, A and B. All chromosomes are paired, so you are either AA, AB or BB. Both A and B have the KIR activator/stimulator receptor gene called 2DS4, but the A haplotype doesn't contain any other stimulator genes whereas the B haplotype contains various combinations of 2DS1, 2DS2, 2DS3, 2DS5, 3DS1 together with 2DS4. 84% of 2DS4 genes are a null allele (so they don't actually activate KIR receptors) which means your body is likely to be less efficient at regulating your NK cell activity. So if you have the AA haplotype, your KIR result will show only 2DS4 and none of the other activators. If you have 2DS4 with other groups, you are AB or BB. It is the AA haplotype that seems to be more more common in women who have repeat miscarriage or repeat implantation failure with IVF, and one study suggested that treating these women with GCSF injections might increase their pregnancy rate (whereas treating women who are AB or BB might drop their pregnancy rate).

Some studies suggest that being AA haplotype is more of a problem where 1 partner (particularly the male partner) has HLA-C2 genotype, or where the female partner has a homozygous HLA-C genotype.

8.2 Gestone (and cyclogest, crinone, utrogestan)- progesterone8.2.1 Why is extra progesterone often prescribed for immune Tx?Ladies with autoimmune issues (often signalled by elevated populations of CD19+5+ cells in the blood) may have anti-progesterone antibody activity and therefore need extra progesterone supplementation to ensure that the their blood levels are high and steady enough to maintain a pregnancy until 12-16 weeks. Progesterone also has anti-inflammatory properties which may also be helpful due to the higher levels of inflammation experienced by ladies with both autoimmune and alloimmune (DQa match) issues. Extra progesterone will not reduce a high CD19+5+ level, but is given as a precaution against one of the consequences of a high CD19+5+ (the primary treatments to try to bring excessive CD19+5+ down are steroids and IVIG (and possibly intralipids).

8.2.2 How are progesterones administered?Most immune docs prefer to prescribe gestone as its absorption is supposed to be more guaranteed than other forms of progesterone and they feel that having a high level of circulating progesterone may be more important for ladies with immune issues due to its anti-inflammatory effect - whereas for 'normal' ladies the concern is generally only for maintainance of the lining for which pessaries normally perform well for most patients. Gestone (progesterone in oil/prontogest/agolutin) is given by daily (or twice daily) injection usually into the upper outer quadrant of the buttock. The generic name for injectable progesterone is 'progesterone in oil' or 'injectable progesterone' but in the UK, the normal brand name is gestone. However, occasionally there are shortages, so products from other countries may be substituted e.g., Prontogest (from Italy) or Agolutin (from Czech), although Agolutin comes in 30mg or 60mg ampoules rather than 50mg like Gestone and Prontogest. It may be necessary to ask your doctor to use the generic name 'injectable progesterone in oil' on your prescription so that you can buy whatever is available rather than finding your prescription is only valid for gestone and then finding that your pharmacy can only source something else like Prontogest. If neither prontogest nor gestone are available in the UK, then Agolutin is normally readily available (on prescription) from Czech pharmacies e.g., pharmacy@pharmawell.eu (contact's name is Slava), and is very economical e.g., 3Eu for 5 ampoules of 60mg.

Cyclogest is given as a vaginal or rectal pessary. Crinone is given as a gel vaginal pessary. Utrogestan is usually given as vaginal pessaries. Most immune docs prefer gestone because its absorption is more certain, but fertility clinics often prefer pessaries because they are easier to use, cheaper, and in mainstream studies (i.e., not specifically for patients with immune problems) show similar effectiveness as injectables. In some cases, a combination of gestone and pessaries will be used.

Progesterone supplementation is normally started from the day of egg collection/ovulation or 3-5 days before FET and is normally stopped at twelve weeks for immune treatment ladies. Some IVF clinics will suggest stopping it much earlier e.g., nine weeks, and if you are bleeding or have significant autoimmune issues, some immune docs will suggest continuing it until sixteen weeks or until you stop bleeding.

Gestone injections are less tricky if you can find another person to give them to you – but you will find videos on youtube showing how to do the shots yourself if you have to. Warming the vial of gestone for a few minutes in your bra just before use may help the injection to sting less and be absorbed better (leading to fewer lumps in your butt). Massaging the injection site with a clean cotton wool pad after the shot can also help disperse the shot. Its better to have two needles for each shot (so you can use one needle for drawing up the injection, and then a fresh (sharp) needle for the shot) but it is not essential. You can buy boxes of 100 needles and syringes without a prescription from medical supply companies like medisave.co.uk (which tend to work out cheaper than buying in smaller quantities from the pharmacy. I have often found that pharmacies are out of stock of large needles and syringes – for gestone 2/2.5 ml syringes are often used with 21 gauge (green) 1&1/2” needles but some clinics say you can get away with smaller gauge needles particularly if you are skinny. The needles do look very large, but in practice, your bottom is less sensitive than other areas of your body so gestone shots are actually less painful than, for example, humira or clexane shots that use a much smaller needle.

If you are taking more than one shot per day or are taking pessaries and shots, its best to spread them evenly throughout the day and not vary the time too much to keep your progesterone levels even (as this may be more important for ladies with autoimmune issues than for ‘normal’ ladies). If you develop rashes or other allergic reactions from any of the progesterone products, discuss it with your consultant because you may be able to switch to something without the allergen (e.g., peanut etc).

If you are concerned that your progesterone level may be an issue, you can ask your doctor for a progesterone level test, say, 2 days after you start your progesterone supplements and then again on a positive pregnancy test.

Personally, I feel safer that I am not introducing any infection if I wash my hands with surgical scrub (e.g., hibiscrub from the chemist or cheaper from medical supply companies) before inserting pessaries, and before all injections I use a pre-injection wipe (also cheaper from medical supply shops), but you can also use cotton wool with surgical alcohol.

8.2.3 Can progesterone prevent a threatened miscarriage?This is controversial as many doctors would say that if the body’s progesterone is dropping that is a sign that miscarriage is inevitable and there is no point in increasing progesterone medication. However, immune fertility docs believe that dropping progesterone may be due to autoimmune issues, in which case adding extra progesterone may help. Consequently, if you find you are bleeding/spotting in early pregnancy, conventional clinics may tell you there is no point in increasing your progesterone dose, but you may get different advice from your immune consultant. If you do increase the dose, personally, I think its important to stay on the higher dose as varying the dose down may make your levels unstable and, for ladies with autoimmune issues, more likely to trigger bleeding until you’ve got past 12 weeks of pregnancy.

8.2.4 How much does gestone cost?The cost price is about £4.50 per ampoule (either 50mg or 100mg – but the 100mg ampoules are often hard/impossibleto source). Different pharmacies will charge different mark ups on this. By contrast, pesssaries are much cheaper – cost price about £10.58 for 15 x 400mg pessaries.

8.2.5 Can you take too much progesterone?

Studies on progesterone levels in medicated donor egg recipient cycles show a lower pregnancy rate if the recipient is using high doses of vaginal progesterone in the first 2-3 days. This suggests that having too much progesterone prior to implantation can 'overmature' the lining. However, later on (e.g,. after 5 days), high progesterone levels are unlikely to be a problem and may be helpful. This study suggested that for one group of donor egg recipients, starting on 200mg vaginal progesterone (twice a day) and then increasing the dose to 400g (twice a day) after 5 days gave a better pregnancy rate than starting on 400mg (twice a day). With 50mg (once a day) intramuscular progesterone, even though the blood levels of progesterone were higher, there was no reduction on pregnancy rate, suggesting that whilst high starting doses of vaginal progesterone may be a problem, intramuscular progesterone may not be quite so much of a problem.

For ladies who are concerned that their progesterone levels in IVF cycles may be sub-optimal, the logical approach would seem to be to start on the minimum amount of progesterone that they think is likely to be needed and test the blood level before embryo transfer to check it is not very low or very high before stepping up the dose if necessary (particularly if they have bled before test day on previous cycles) and/or to use intramuscular progesterone instead of vaginal.

HCG is used as to mature the eggs prior to egg collection in fresh IVF. During IVF (and often during IUI cycles), agonist (e.g. buserelin) or antagonist (e.g. cetrotide) medication is normally taken to prevent the LH surge and therefore ovulation, so either HCG or LH needs to be taken in order to allow the eggs to be released from the follicles either naturally for IUI or by needle aspiration for IVF. HCG is used because its cheaper than LH.

However, there are other uses for HCG. Some clinics use it as well as or instead of progesterone support after embryo transfer. Occasionally, its used as 'rescue therapy' if there is a positive pregnancy test but the HCG levels do not rise naturally at a good rate (at least 66% every 48 hours initially). This rescue therapy has a low chance of success but does work occasionally and is cheap (3 shots of 1500 IU given on alternate days - each shot costs £2- £3.

Some studies have suggested that HCG can also improve implantation rates e.g.,

Many US clinics have used HCG shots as part of luteal support for many years.

9.2 Humira9.2.1 What is Humira? What is it used for in fertility treatment?Humira is a drug that was designed to block TNFalpha in conditions like rheumatoid arthritis, Crohn’s disease and ulcerative colitis. It is used by some fertility doctors to reduce elevated TNFa detected in the blood or uterine NK cells (CD57+) detected by uterine biopsy (which are both associated with a lower chance of live birth). Humira is an expensive drug - about £750 for a course of two shots – Healthcare at Home (08702 400518 – ask for Jade Herrington) are often the cheapest pharmacy to buy it from. Ladies who have an underlying diagnosed autoimmune disease like RA, Crohn’s or UC might be able to get their NHS consultant to prescribe Humira on the NHS for their medical condition but also get an improvement in their fertility.

9.2.2 How is Humira given?Humira is given in courses of two subcutaneous injections, usually two weeks apart. It is usually prescribed in a packet of 2 prefilled syringes or 2 prefilled pens and MUST be kept refrigerated otherwise it degrades and becomes useless. It is usually delivered to your home in a polystyrene ice box. A video for how to do do the pen style injections can be found on the humira website. http://www.humira.com/global/injecting-humira-pen.aspx. Some ladies find that icing the site beforehand helps it not to sting. Also, taking the packet out of the fridge 5-10 mins before using it to let it come up to room temperature may help too.

9.2.3 What the risks/side effects of Humira?TNFa is part of the body’s mechanism for protection against viruses, some bacteria and cancer. It is unlikely to be prescribed to anyone whose levels are not high, so hopefully it should only be reducing TNFa levels down to normal. It is common to catch minor colds/get sore throats on Humira and it does raise the risk of becoming vulnerable to TB infection (see below). As with steroids, you should try to avoid anyone you know is infectious (e.g., children with chickenpox) unless you are sure you are immune, and if you do have any reason to think you have picked up an infection (or start getting TB symptoms) you should seek medical help. You should also delay starting Humira if you know you have an infection. Skin rashes at the injection site are also common.

Humira is a new drug, and as for almost all new drugs, it has not been tested on pregnant or TTC women for ethical reasons. Accordingly, there is no rigorous proof that it is safe for the unborn baby. The manufacturer recommend that it is not taken within five months of pregnancy (to ensure all traces of the drug have left your system before conception). However, it has been taken by a number of women either who were unaware they were pregnant or whose illness was so severe that the benefits were judged to be worth the risk. It has also been used in fertility treatment for several years in the US by various clinics and by the ARGC, Care Fertility and Dr Gorgy in the UK. So far there is no evidence that it has any significant links with causing problems for the unborn baby.

9.2.4 Why do I need a TB test before Humira?It is possible to have latent TB without developing active TB, but Humira can allow latent TB to become active. It is therefore important to screen for TB before taking Humira and, if you are found to be positive for TB, you should get medical advice on whether it is appropriate to take antibiotics to deal with the TB before starting Humira, whether it is better to avoid Humira altogether or whether to proceed with Humira but be monitored for any development of TB (the decision will depend on your age, general health and whether the TB is active or latent). The most convenient and accurate test is usually the Quantiferon TB gold test or the TSpot TB test. Tests may be available through your GP, local private hospital or TDL (via Dr Gorgy/ARGC etc). Not everyone gets a valid response to these tests though as they depend on having good immune function, so in those cases if a retest is also invalid, you may have to resort to a chest X-ray to check for TB or speak to an immunologist or other doctor to assess your risk of TB.

9.2.5 When should I retest my cytokine ratio after Humira?There is no straight answer to this because the duration of the effect of Humira varies a lot between different people. Anything between 1-3 weeks may be recommended by your consultant. If the level has not reduced after the first two shots, you may be recommended to have further shots. Some ladies find that their levels increase (‘flare’) following Humira and where this happens you will need to discuss with your consultant whether it is better to take further shots or, possibly, to take IVIG instead.

9.2.6 How long does Humira last in your system? How long before my treatment should I take it?To be completely clear of your body, the manufacturers recommend five months. Obviously if you are taking it for fertility reasons, you are trying to get pregnant whilst it is still in your body and actively bringing your TNFa (and uterine NKa) down, so there would be no point in taking it and then waiting for it to leave your body before trying to conceive. In patients using it for rheumatoid arthritis, the length of symptomatic relief is very variable from person to person. Some patients find they have to use it every one or two weeks to keep on top of their symptoms. In fertility treatment the last shot of Humira tends to be taken about 2-6 weeks before the stimulation part of the cycle starts to maximise the chance of it still being effective but to allow time for retesting and for any initial side effects to have resolved. A longer (or shorter) period before cycling may be recommended by your consultant e.g., if your TNFa is not very high and/or you have egg quality or other issues that a TNFa reduction may help with but needs time to act on.

9.2.7 How much does Humira cost?I think its about £720 for 2 shots – delivered to you from Healthcare at Home (see Resources below).

9.2.8 Do I have to have Humira? Can I get/stay pregnant without it?Obviously the total number of ladies taking Humira for fertility around the world is very small so most ladies do get pregnant without Humira. Some immune docs don’t use it all. E.g., Dr Sher at SIRM has previously said on his forum that he does not prescribe it because the studies on its use for fertility so far are too small to justify its use given that it is such a new drug so there is always the possibility of as yet unknown problems for the baby conceived following its use. That said, he is operating in the US where as I understand it, access to surrogacy as an option may be easier than in the UK, so he may be quicker to suggest moving on to surrogacy rather than using more aggressive treatments. He prescribes steroids plus intralipids for high TNFa or uterine NKs. Serum in Athens prefer not to use it either. Dr Ndukwe at Care, tends to follow Dr Sher's protocols, although he will consider Humira for ladies who request it, particularly if they have already tried steroids plus intralipids without success. The ARGC, Beer centre and Dr Gorgy use it routinely, partly because it is a fairly strong drug so is very effective at dealing with aggressive uNKs or high TNFa for most patients, but also because the alternative medication (IVIG) will usually work out more expensive as it is a more expensive drug and will usually need to be repeated at intervals during fertility treatment and pregnancy. However, if you decide you do not want to take Humira, you should always feel that it is your choice, and if you want to try less aggressive treatment first, e.g., steroids plus intralipids or an alternative regime of steroids plus IVIG, ideally your consultant should let you have those options. Similarly if you cannot take Humira for medical reasons e.g., due to TB or serious immune suppression, I feel that there is still a good chance to achieve a live birth with other drugs especially IVIG.

Other alternatives to think about are:

intralipids with steroidsresveratrol (see supplements), omega 3 fish oil, turmeric/curcumin, nettle, green tealosing weight (if you are overweight)changing your diet (e.g., if wheat or dairy makes you feel bloated and uncomfortable and avoiding it makes you feel better, then that may tie in with reducing your TNFamaking sure you aren't carrying a long term infection (e.g., see Chlamydia)some ladies have also been successful with mycology/chinese herbal medicine under specialist docs like Dr Trevor Wing.

10 I 10.1 Insulin resistance/gestational diabetes/polycystic ovaries10.1.1 Should I be tested for insulin resistance?In my opinion if you are TTC and have signs of polycystic ovaries, a family history of diabetes or are obese, you should ask your GP for a glucose tolerance test (or get it done privately, e.g., at TDL) to determine whether you are insulin resistant. This will establish whether taking metformin might help you become less polycystic and hopefully improve your egg quality. It may also be important to protect your future health by identifying risk of diabetes.

In pregnancy, immune Tx ladies may have a higher than average risk of developing gestational diabetes because of often being over 35, having PCO, being overweight, having a family history of diabetes (which is linked to autoimmune genetic tendencies) and because of the slightly increased risk of increasing any pre-existing insulin resistance after taking steroids and/or intralipids. Once you start seeing a midwife in the UK, you will have periodic urine tests for glucose in your urine but these are notoriously unreliable at identifying gestational diabetes. Undiagnosed gestational diabetes can have serious consequences for your baby. Accordingly, if you think you are at increased risk, I think you should ask your GP/midwife for a glucose tolerance test before the end of the 1st trimester and then repeat it at least at the end of the 2nd trimester, and possibly again one month later.

If you are diagnosed with gestational diabetes you should get advice on a low GI diet and be very strict about it. You will also be told to self-monitor your blood sugar several times a day and be prescribed metformin and/or insulin. The doses may need to be increased as your pregnancy progresses so you would expect to be seeing an antenatal diabetologist regularly during pregnancy. After pregnancy, it is very likely that your insulin resistance will return to your normal level, but there is a high risk of developing diabetes within a few years.

10.1.2 What can I do about insulin resistance/PCOS?If you have any excess weight, its important to lose it to help your fertility and reduce insulin resistance. A low GI diet (avoiding foods containing sugars or simple starches (white flour, pasta etc), and cutting down on sugary fruits and juices) can help stabilise your blood sugar levels. Exercise can also help.

The medication metformin is often prescribed to reduce insulin resistance. It is usually started at a low dose and then gradually increased (to avoid digestive discomfort). However, it is not always obvious what dose you need to take unless you monitor your blood sugar periodically to see whether your sugar levels have normalised. Severe insulin resistance is diabetes and if you are eventually diagnosed with diabetes, even high doses of metformin may be insufficient and insulin may be necessary.

Home monitoring of your blood sugar levels is very simple using an over-the-counter blood glucose testing kit available from any pharmacy. The kit will come with a small pack of testing strips. If you diagnosed with diabetes, then you can get further testing strips (and lancets – the finger prickers you need to use) on the NHS. To test for insulin resistance, you need to test at least twice – a ‘fasting’ test before breakfast and another test two hours after eating. You can see normal ranges for blood sugar levels in the NICE guidance on diabetes on the internet.

There are studies that suggest that PCOS and insulin resistance are more common in ladies with elevated PAI-1. A tendency towards high PAI-1 can be genetic - see Thrombophilias.

10.1.3 What is a suitable low GI diet for pregnancy and why might I need to use one?

Unfortunately, gestational diabetes (GD) is very common, especially amongst ladies who have immunology treatment because1) they tend to have risk factors for GD - being over 35, having PCOS, being overweight, having a history of diabetes in the family2) they tend to have corticosteroid and/or intralipid treatment in pregnancy both of which may increase your chances of developing GD

High blood sugar levels during pregnancy increase the risk of miscarriage and stillbirth, so you may want to take every precaution you can to keep your sugar levels stable from as soon as you get pregnant, although most commonly, gestational diabetes tends not to kick in until pregnancy hormones and weight gain get very high e.g., from 18 weeks of pregnancy onwards.

You can find a lot of information on the glycaemic index/glycaemic load of different foods on the internet to help you find low GI/GL foods but the type of strict diet you may find works to keep your blood sugars stable may look something like this:

breakfast: small bowl of sugar free wholegrain cereal e.g., shredded wheat or soya bran based cereal - or 1 egg and 1 slice of soya&linseed toast. no fruit or fruit juice especially if your pre-breakfast blood sugar tends to be high - otherwise, you might try a small handful of berries or an apple.

tips: you may need to keep tweaking your diet as you get bigger and depending on your personal daily blood sugar pattern e.g., if your pre-breakfast sugar level is high - you may need to cut down your night time snack, whereas if your post-meal sugar level is high, you might need to avoid having fruit for desert etc. fruit juice and smoothies are very sugary. the lowest GI fruits tend to be apples and berries (strawberries, blueberries etc). most breakfast cereals are very sugary even muesli because of all the sultanas etc. adding protein to carbohydrates slow the absorption of sugar so eating cheese with fruit or ham with melon should give a lower blood sugar level than eating fruit on their own. adding lemon juice or vinegar to carbohydrate helps to slow its absorption and reduce its effect on your blood sugar, so potato salad made with barely boiled new potatoes and a lemony dressing will be lower GI than, say, a baked potato. if you get desperate for a chocolate fix, try a single chunk of dark chocolate, chocolate flavoured sugar free 'angel delight' type deserts (if you have to), or splurge on a very occasional low carb high protein chocolate bar (the kind body builders use - sold in health food shops).

10.2 Intralipids10.2.1 What are intralipids? What do they do?Intralipid is a solution of soybean oil in saline, stabilised with egg yolk extract. It looks like milk and comes in an IV bag. It has been shown to reduce NKa in patients whose NKa is elevated. In studies of patients who are immunosuppressed it has been shown to raise NKa. It is therefore believed to be immuno-modulatory rather than immunosuppressant. The mechanism of how it works is unproven, but it is believed that shifting the lipid balance towards ‘good’ unsaturated fatty acids away from ‘bad’ saturated fats may modify the signalling mechanism to NKs. Logically, if elevated NKa is causing elevated TNFa, reducing NKa should also reduce TNFa.

10.2.2 How long do the benefits of intralipids last?Studies have shown that normally, the effect of intralipids on NKa lasts for 4-6 weeks.

10.2.3 Who can’t have intralipids?Ladies who are allergic to soya, peanuts or eggs may suffer an allergic reaction and are therefore usually advised not to have intralipids.

10.2.4 What are the risks/side effects of intralipids?Most ladies have no side effects. The only serious risk is that of allergic reaction (but the risk is low so long as you are not allergic to soya, peanuts or eggs). It will also raise your blood lipid level which may affect ladies with poorly controlled diabetes or insulin resistance. With pregnancy there is always a risk of developing gestational diabetes (a very common condition which usually reverses after pregnancy) particularly for ladies who have PCOS, who are overweight, older or who have a family history of diabetes, and the risk increases towards the end of the second trimester. In the UK, pregnant ladies are monitored for gestational diabetes using urine testing but this is very inaccurate, so ladies who have these risk factors and who are continuing to use intralipids after the first trimester might want to ask for additional screening for gestational diabetes so they can make the doctor who is responsible for their intralipid treatment aware of any increased risk of diabetes.

10.2.5 How are intralipids given?Intralipids are diluted in saline solution usually just before they are given (often by injecting the contents of a bag of concentrated intralipid into a much larger bag (or IV bottle) of saline e.g., starting with a 500ml IV bag of saline, 100mls is withdrawn by syringe through the 'port' and discarded so that 100mls of intralipid can be injected before shaking the bag gently to mix it). You need to have a cannula fitted in the back of your hand or in the crook of your elbow, and then the intralipid is infused in by IV over 1-2 hours. Intralipid is more viscous than IVIG so a 22 guage blue, 20 gauge pink (or larger 18 gauge green) cannula is normally used. The dose does not tend to vary by the weight of the patient as it is less critical than for IVIG because its much cheaper. Dr Gorgy, SIRM and Care tend to use a dose of 100mls 20% intralipids diluted in 200-500mls of saline but other clinics may use lower or higher doses, and I have heard that some clinics overseas give intralipids 20% undiluted either 100mls or even 500mls. According to Dr Sher, it is important that the intralipids are diluted before use because the undiluted solution can cause irritation. I do not know whether any irritation caused by undiluted intralipids would be enough to cause inflammation of the kind that would increase levels of TH1 cytokines or not, or whether it would be just a minor annoyance. The antihistamine pre-meds that are sometimes given with IVIG (see below) are not usually given with intralipids. Intralipids do not usually need to be refrigerated.

ProtocolDoseage: Intralipid 20% 100mlsRoute: IV - over 1-2 hours. Due to viscosity it is recommended that a 22 guage (or above) cannula is used. Administration: In 500mls or 200mls 0.9% Sodium chloride. 1: withdraw 100mls saline and discard. 2: add 100mls 20% intralipid to remaining sodium chloride.Day of treatment: Administer 7-14 days before embryo transfer. If patient has a positive pregnancy test following treatment, she should have further treatments every 3-4 weeks as prescribed by her doctor. Drug: Intralipid. Sterile fat emulsion. Store below 25degrees. Use immediately after dilution.Contraindications: Hypersensitivity to egg- soya- or peanut-protein or to any of active substances or excipients.Toxicities: Intralipid contains egg and soya which may rarely cause allergic reactions. Fat metabolism may be disturbed in conditions such as renal insufficiency, uncompensated diabetes, pancreatitis, certain forms of liver insufficiency, metabolic disorders and sepsis. Intralipid may cause occasional rise in body temperature.Pre-treatment bloods: noneBlood tests required during treatment: noneNumber of planned visits: As per patient registration/referral. If positive pregnancy result post infusion, some consultants will prescribe every 3-4 weeks for up to 31 weeks of pregnancy.

10.2.6 Can I have intralipids administered outside of London?If you are having treatment with Dr Gorgy, obviously he prefers you to have drips in his clinic (and drips are usually available to ladies who need them urgently very quickly if you attend the clinic), but if this is impractical for you, he is usually able to provide a prescription for you to arrange for HealthCare at Home (08702400518 – ask for Jade Herrington) to administer. Healthcare at Home have a UK wide team of nurses who will come to your home and administer it to you. A few UK IVF clinics may agree to administer it (but I haven’t heard of this happening very often) and even a few GPs. You may be able to find a local nurse through a nursing agency who can canulate and administer intralipids - see below.

10.2.7 Can I have intralipids administered on a weekend?Healthcare at Home will administer it on a Saturday subject to availability but they charge extra. Dr Gorgy will usually administer it on a Saturday provided you book in advance (on weekdays, for a drip, he can often fit you without an appointment at short notice) and have a fairly early appointment so that it is finished well before lunchtime.

10.2.8 How much do intralipids cost?The actual cost of the drug and consumables is only about £20, but the cost of nursing care to receive it (a nurse has to give it to you by IV and be on hand in case of any problems) adds a lot to the cost. With Healthcare at Home the total cost of intralipids is currently about £380 by debit card (although there is an extra fee to pay by credit card). With Dr Gorgy intralipids is currently about £350.

According to their website, CMRW offer intralipids for £250. Midland Fertility Services are another option.

If you are having IVF abroad, it is worth checking whether its available there because in some countries nursing costs are much cheaper. If you happen to have a nurse or doctor in the family who is prepared to administer it for you, then you may be able to get it for just the cost of the drug and consumables (saline, giving kit, cannula, syringes for mixing etc), but of course you would need someone who is prepared to write the prescription for you and, of course, Dr Gorgy (and Healthcare at Home) are experienced in preparing and giving intralipids, so you may prefer to have your first drip with Dr Gorgy. Some ladies have managed to find a local nurse e.g., through a nursing agency (e.g., Medihome, Allied Nursing, Prestige Nursing, Advantage Healthcare), which has worked out signficantly cheaper than Healthcare at Home but they have had to obtain the intralipids, saline and consumables and have had to satisfy the agency's requirements in terms of written instructions from a (UK) doctor and risk assessment.eSome ladies have had intralipids with Verona Hall in Dulwich which costs about £100 excluding the intralipids but including saline and consumables. http://www.veronahall.co.uk/. In London there is also medihome who charge £195 excluding the intralipids.

Health Professionals http://www.healthprofessionals.com can apparently give an infusion for about £140 excluding the intralipids and consumables but I don't know if they only cover the London area. The contact name is Michele Jogee and you may have to pay a one off charge for a health and safety assessment. In East london www.theoaksclinic.co.uk do intralipids for £150 including the intralipids and consumables.

Boundtree medical (www.boundtree.co.uk) has been recommended by at least one lady as being able to supply consumables in small numbers as opposed to other supplies like medisave.co.uk who only supply kits of 50. Intralipids and saline are available from many pharmacies e.g., Rigcharm, Boots, Superdrug, ASDA, but many pharmacies are reluctant to supply single 100ml bags because they can only be ordered from the manufacturer in packs of 10. The alternative is to ask for a prescription for 10 bags of 100ml intralipids so that you buy a whole pack at once and then plan on using the rest for future drips, or ask for a prescription for a 250ml (or even 500ml) bag because those come in singles - although you will have to discard anything unused as it cannot be saved and used for a future drip. 500ml bags of saline are also more commonly supplied than 200ml bags so you may find its easier if you can ask for the prescription to state 200ml, 250ml OR 500ml so you can buy whatever is available. Because of the (very unlikely) chance of a severe allergic reaction, a doctor or nurse giving intralipids will normally carry antihistamines (e.g., piriton tablets) and epinephrine (epi-pen etc).

If you do arrange an agency nurse, the agency may require you to ensure that that the antihistamines (e.g., 2 ampoules Chlorphenamine/chlorpheniramine (10 mg/mL) 1ml, 2 ampoules of adrenaline 1:1000 (1mg/ml) 0.5ml and 2 ampoules of efcortesol (100mg/ml) 1ml are available, and 6 syringes 1ml & 6 needles, which means asking your doctor for a prescription for these and purchasing them so they are available in case of an emergency.

10.2.9 How often do I need intralipids?Studies have shown that the effect on NKa suppression lasts 4-6 weeks. However, Dr Sher recommends intralipids every two weeks for DQa match (alloimmune) problems, and Dr Gorgy tends to vary the time between drips depending on the severity of your immune issues and what your NK retests show. The first drip is normally given 7-14 days before planned ET or implantation. Further drips are normally given on BFP and on first scan (6.5 weeks). After that, the treatment plan will vary depending on your consultants’ advice.

10.2.10 When do I stop intralipids?Dr Sher and Dr Ndukwe stop intralipids at about 22 weeks (sometimes earlier e.g., 12 weeks if there are simple immune problems that respond well to treatment, but longer for DQa match problems with raised NKa). Dr Gorgy tends to continue it until about 31 weeks by which time, even if there is a significant immune ‘flare’, the baby should be developed enough to reach almost full term before it is affected by an immune flare. My expectation would be that most pregancies are well enough established to resist immune attack if the intralipids are stopped at 12 weeks, but in a minority of cases it may help if the drips are continued until 22 weeks. Similarly, almost all pregnancies will be strong enough to stop intralipids by 22 weeks but there may be a tiny minority who would benefit from intralipids until around 31 weeks. The difficulty is knowing whether there is likely to be any benefit to you from continuing past 12 or 22 weeks and I think you can only use your past history and your doctor's judgement to guide you on that decision.

10.2.11 What supplies do you need?The kit will often include an IV bag (or an IV bottle) of intralipid e.g., 100mls of 20% intralipid solution, a large e.g., 500ml, IV bag/bottle of saline for dilution, two 50ml sterile syringes with needles (one for removing saline and the other for adding intralipid to the large bag/bottle), an IV giving kit (the spike that attaches to the bag/bottle with a length of tubing including a flow rate valve that attaches to the cannula) and a 22 guage (blue) cannula. The kit may include two small e.g., 50ml, bags of saline for flushing the IV line before and after the intralipids, antiseptic swabs for wiping the cannulation site), latex gloves, sterile drape (for standing all the bits and pieces on), adhesive tegaderm film or micropore tape (for sticking the cannula in place), large sharps bin (for disposing of all the IV bits after use - you will need to check the facilities in your local area for disposing of sharps' bins - in some areas it is arranged through GP surgeries but in other areas it is through the local council etc) and sterile cotton wool balls (for pressing against the cannulation site after the cannula has been removed) - or the nurse may have all or some of these. The nurse will usually have a drip stand (you can improvise this if needed by hanging the drip bag from a hook (from the ceiling, wall, door etc - within easy reach of where you will be sitting) and high enough so that the bag will be at least 3 feet higher than your heart, thermometer (to check your temperature periodically to make sure that you aren't having a fever reaction to the infusion) and blood pressure monitor (to check periodically in case there are signs of an allergic reaction). Some nurses will also use an electronic IV pump to control the flow of the drip automatically, but it can be controlled manually using the standard valve on the giving kit.

You may also have to arrange written instructions from your doctor, and oral antihistamines and epinephrine (on prescription from your doctor) if your nurse cannot supply these.

You will also probably want a drink and a snack.

10.2.12 Can I work whilst the drip is given?You will usually be able to move around with care, taking the drip with you and will have one hand/arm free to use the phone etc. Healthcare at home may agree to come to your workplace, and although the nurse will stay with you until the drip is removed, you are free to carry on working if you want to.

10.3 IVF10.3.1 Can I have IVF with my NHS clinic/local clinic/abroad but still have specialist immune treatment?Yes. See Appointments (above) but Dr Gorgy and AEB are usually happy to work alongside other IVF clinics.

10.3.2 Does it matter where I have IVF or what protocol is used?Different clinics will have very different success rates. This will partly be due to the quality of their embryology department, partly due to the protocols/stimulation regimes they use and the skill and experience of their doctors in gauging the best drugs and doses to prescribe and partly due to how much care/attention they can devote to monitoring you during your stimulation to optimise your drugs and doses and the timing of your egg collection.

testing all patients for ovarian reserve - FSH, AMH and antral follicle testsscreening for endometrial defects, and hydrosalpinges - using saline scans, hysteroscopy, etcuse of a mixed LH and FSH stimulation protocol - rather than 100% FSH (e.g., gonal F) - it is common in US clinics to make variable mixes of FSH and LH (e.g., 80% gonal F plus 20% Luveris), rather than relying on a fixed 50:50 mix like menopur.step down dosing - starting on a reasonably high dose of stimulation drugs and then monitoring closely and reducing as necessary (rather than using a lower dose and increasing it if response is poor)ultrasound guidance for ETselective use of ICSI, culturing embryos together in microdropsuse of blastocyst ET in selected cases. good air quality using filtration (in the embryology lab) and heated stages for oocyte and embryo work.

There are many different IVF drugs and many different protocols. Many UK clinics insist that drugs are very similar, that the difference between different protocols is insignificant and that the cost/benefit of frequent monitoring during stimulation does not support a case for frequent monitoring. This tends to be the case for NHS clinics who would have to be able to show that there is a significant cost benefit before changing their practices. Other clinics argue that tailoring protocol to the specific patient and monitoring during stimulation is crucial and this seems to show in their success rates because the highest success rates are typically seen at clinics that do very close monitoring during stimulation.

Some US clinics will tend to use higher starting doses of stimulation drugs and, if necessary, to reduce/stop the stimulation drugs after a few days and ‘coast’ you until egg collection, but be aiming for a fairly large number of eggs to be collected. Some European clinics, will tend to use low doses of drugs and aim for a smaller number of eggs to be collected. My experience of some NHS clinics is that the doses used can be quite standardised (not tailored to the patient and not flexed during treatment) leading to some cases of OHSS and some cases of fairly low numbers of eggs recovered even in patients who could expect a higher response on an higher dose. Some clinics will monitor you only by ultrasound on say, 3 days during the later part of stimulation. Other clinics (which do tend to have higher success rates e.g., ARGC) will monitor you daily or even twice daily using a range of blood tests as well as ultrasound, possibly changing your medication every day if necessary. Some clinics will only staff the operating theatre for 2 or 3 days a week so egg collection will have to be done on one of these days rather than to suit the egg development of the individual patient. Similarly if there are only a limited number of surgery slots, it is possible that the timing of egg collection will be determined by operating theatre/staff availability rather than optimal egg development. Some clinics may be closed at weekends, which may mean you are restricted to having an embryo transfer on a suboptimal day for you. (Embryo transfer is usually done on day 2, 3 or 5 after egg collection.

Assuming the clinic are competent to culture as far as the day 5 blastocyst stage, the optimal day depends on how many good embryos are available to choose from. If you have several good embryos on day 2, transfer is usually better being postponed to enable the embryos to develop for longer to try to eliminate the poorer quality ones and distinguish the better ones. The same logic applies on day 3, as it will usually be better to wait for a blastocyst day 5 transfer if the best embryos are not obvious. Transfers are not usually done on day 4 because it is difficult to assess the quality at that stage.)

Clinics like SIRM in the US express very strong opinions about their protocols, advocating for example a specialised version of the short (antagonist protocol) called agonist/antagonist conversion where the patient normally starts off on the pill, then adds buserelin (or another down regulation (agonist) drug) about 5 days before stopping the pill, then when bleeding starts, a half dose of antagonist (e.g., cetrorelix or ganirelix) at the same time as FSH is added and the agonist is stopped. The antagonist is continued (with the stimulation drugs) until HCG trigger day. The advantage of this protocol according to SIRM is that the pill allows the timing of the cycle to be predetermined, overlapping the pill with the agonist causes a mini flare in FSH to recruit a good batch of follicles (not as important for high responders) and the half dose of antagonist (and using mainly FSH-only stimulation drugs i.e., not FSH/LH mixed drugs like menopur) keeps the background level of LH low which they say is important for egg quality in older or PCOS ladies.

Many clinics will suggest trying the long protocol first (as that has tended to have the highest success rates for ‘average’ ladies), but then if you over-respond (too many follicles) and/or have poor egg quality, try one of the short protocols where the number of eggs recovered may be lower, but in some cases, the egg quality may be higher.

Other protocols you may hear about are the standard long (agonist) protocol (where you down regulate with an agonist drug like buserelin on day 21 of your cycle and then start stimulation drugs at any time after your bleed), the conventional short (antagonist) cycle (where you do not down regulate – although sometimes prepare for your cycle on the pill – and start stimulation drugs on day 1-5 of your bleed and then add an antagonist (e.g., cetrorelix or ganirelix) either when your lead follicles reach about 12mm or on a fixed day (e.g., day 7) of your stimulation to prevent ovulation, or the ‘flare’ protocols where you start a down regulation drug like buserelin at the beginning of your cycle to induce a ‘flare’ in FSH shortly before or at the same time as starting stimulation drugs. Whether one protocol is superior to another for all ladies is very difficult to determine, but it seems reasonable that some ladies will suit a particular protocol more than others. So if you do have issues with over or under responding or with egg quality, it may make sense to get at least one second opinion on what protocol might suit you better.

Even on a simple long protocol with a single stimulation drug (e.g., menopur, gonal F, puregon, follistim etc), different clinics may have different views on the dose of the down regulation drug to use for you. All the agonist drugs (the down regulation drug - buserelin (synarel), triptorelin(decapeptyl), naferelin, leuprorelin (lupron)) are very similar, but doses of agonist have traditionally been high - about 500mcg (0.5mg), but some clinics are now favouring much smaller doses e.g., 100mcg (0.1mg) or 50mcg (0.05mg), particularly for poor responders as they feel it is not necessary to down regulate the patient quite so fully. Some clinics favour a step down dose of the agonist e.g., starting on 500mcg but dropping to 250mcg on the first day of stimulation or starting on 300mcg but dropping to 150mcg etc.

Similarly, the two antagonist drugs - orgalutran/ganirelix and cetrotide/cetrorelix have virtually identical effect, but some clinics favour lower doses started earlier whereas other clinics favour higher doses started later.

10.3.3 What is the long protocol? The Short protocol? The A/ACP? Mini-IVF? Micro flare? Estrogen priming protocol

The most basic protocol is the long protocol. It has shown the highest success rates historically for 'average' patients.Generally, you start on day 21, taking an agonist (down regulation drug e.g., buserelin, synarel, lupron) by injection or by nasal inhaler. After a brief surge, this drug shuts down your reproductive hormones so that your body's production of FSH (which causes follicles to develop) and LH (which triggers ovulation) is shut down. Once the empty follicle (corpus luteum) resulting from your last natural cycle has broken down, your period starts and the lining is shed which allows your clinic to start you on stimulation drugs at any point from then on. You continue the down regulation drug when you start the stimulation drugs to prevent your body making its own LH and triggering ovulation. Stimulation drugs are normally given by injection every evening until an ultrasound scan shows that the follicles have reached a certain size - at which point you are advised to take a trigger shot of HCG to ripen the follicles. About 36 hours after the trigger shot, the eggs are recovered from your ovaries under sedation/anaesthestic and are used for ICSI/IVF. The resulting embryos are returned to your uterus 2, 3 or 5 days after fertilisation. The long protocol is sometimes recommended for ladies who have a short luteal phase because a short luteal phase may mean that the next batch of follicles are tending to start to mature during the luteal phase - starting down reg on day 21 should prevent this.

The short antagonist protocol is normally started on about day 1 of your natural cycle or on the withdrawal bleed from taking the pill. There is no down regulation, so you start stimulation injections straight away. When scans show that the follicles are large enough to risk ovulating (or sometimes on a pre-set day e.g,. day 5-7), you start an antagonist drug (e.g., ganirelix/orgalutran, cetrorelix/cetrotide) which shuts off your LH to prevent ovulation. When the scans show the follicles are large enough to use for IVF you take the trigger shot and then egg collection proceeds as for the long protocol. This protocol tends to produce fewer eggs than the long protocol, but they may be better quality so its often used for ladies with poor quality eggs or with PCOS.

The microflare protocol is a short protocol where agonist (lupron, synarel, buserelin etc) is started on about day 1 of natural cycle or pill withdrawal bleed, usually in a low dose, and the stimulation drugs are started at about the same time or shortly afterwards. The agonist produces a small flare of FSH (and LH) before it shuts down FSH and LH production and this flare of FSH adds together with the FSH in the stimulation drugs to increase the total dose of FSH available to stimulate the follicles to grow. After the initial flare, the agonist acts as normal to prevent the LH surge and therefore prevent ovulation. This protocol is promoted as possibly being good for ladies who are poor responders but some docs say it is detrimental to egg quality, so some docs will only use it for younger poor responders or not at all. It is also sometimes used as an economy measure for normal responders as it reduces the amount of expensive stimms drugs that are needed by using some FSH from your own body.

The agonist/antagonist conversion is a short protocol where agonist is started about 5 days before stopping the pill to produce a microflare of FSH (and some LH), then on day 1-3 of the pill withdrawal bleed stimulation drugs are started and a half dose of antagonist is started. The agonist drug is stopped at the same time. The half dose antagonist is continued until trigger day. This protocol is promoted as being better for ladies with PCOS or who are poor responders/have poor quality eggs because it keeps the level of LH low, although SIRM use it for most of their patients and I believe its also commonly used by SERUM.

Estrogen priming protocols are sometimes used for ladies who are poor responders (poor response is normally defined as less than 4 follicles in a previous IVF cycle). Estrogen suppresses natural FSH levels (which are usually elevated in ladies with poor ovarian reserve and poor egg quality). Suppressing FSH this way, is supposed to be more 'gentle' than FSH suppression using agonist (buserelin, synarel etc) or antagonist (ganirelix, cetrorelix) because it doesn't produce an initial flare of FSH. The FSH suppression is supposed to help you start your IVF cycle by effectively 'quieting' your ovaries, to allow a clutch of follicles that are all at a very similar stage of development to be recruited when stimulation eventually starts, making it easier sometimes to stimm for a little longer at a lower dose with the aim of producing a maximal number of good quality eggs, rather than having a few lead follicles only. According to Dr Fisch at SIRM, estrogen priming may help to upregulate FSH receptor numbers on the granulosa cells in the ovaries, to make the ovaries more responsive to FSH when stimms are started. It is similar to a pill start protocol, but the estrogen level being aimed for is significantly higher, and there is no progestin (unlike in the BCP). The higher estrogen level is also supposed to protect the developing eggs from damage due to circulating male hormones and is necessary if it is going to reduce FSH levels. The estrogen is prescribed as skin patches, injections or pessaries and started before stimulation begins, usually in the same cycle as your IVF. For example, you might start with the pill (purely to enable scheduling of your IVF for convenience), then start agonist (e.g., buserelin) about 4 days before you plan to stop the pill. When your period starts (due to stopping the pill), the agonist is stopped and antagonist is started at a half dose (continued until trigger day) and you have a blood test for estrogen (E2) level. Provided it is low enough (below 70 pg/ml - which indicates that there are no remaining functional cysts), you start estrogen e.g., 4mg estrogen valearate injections every 3 days (continued until about day 7-9 of stimulation). Stimulation drugs are started after about 5-7 days of estrogen. Estrogen is sometimes continued right up to HCG trigger day

10.3.4 What is the best stimulation drug?

No single drug has been proven to be the best for all ladies. The cheapest drug is usually menopur which contains natural FSH and LH extracted from human urine (in an equal ratio i.e,. 75 iu of FSH and 75 iu of LH per vial). Some studies have suggested it may be more effective for some ladies than synthetic FSH, possibly because it is natural. Merional is almost identical to menopur but produced by a different company and claimed to have a slightly more reliable content of FSH and LH. Fostimon is natural urinary hormone but has been purified to remove LH. Some doctors say that it may produce better quality eggs in ladies who are oversensitive to LH (e.g., older ladies or ladies with PCOS). Some doctors prefer synthetic hormones because they say that the urinary derived hormones can have variable doseages per vial. Gonal F is a synthetic version of FSH that is derived from genetically modified hamster cell culture lines. Puregon is a similar product to gonal F. Neither Gonal F nor Puregon contain any LH. Pergoveris is the same product as Gonal F but with the addition of a half ratio of synthetic LH (i.e., 150iu of FSH and 75iu of LH per vial). The natural FSH's have a reputation for being more gentle and the synthetic FSH's have a reputation for being more aggressive.

In a natural cycle, FSH tells antral follicles in the ovaries to start to grow, this process produces estrogen which is a feedback signal that gradually tells the body that the follicles are developing, and puts a limit on how much FSH needs to be released, and also causes the body to release more LH, eventually leading to the LH surge that triggers ovulation. In an IVF cycle, the stimms injections supply far more FSH leading to the full growth of many more follicles than on a natural cycle. These follicles grow in the presence of natural LH. On a long protocol cycle, or after the first few days of a short flare protocol, LH levels are at an artificially low level. Many doctors think that some LH is needed to help the follicles grow normally, so many IVF patients will grow a better crop of follicles if some LH is included in the protocol so they either use only menopur/merional or use a mixture of drugs including some menopur/merional/luveris/pergoveris with some pure FSH (e.g., gonal F, fostimon or puregon). Although, on a short protocol, the body will have its own background level of LH at least for the first few days, so it may be less important to add LH on a short protocol. Good responders are likely to have a reasonable crop of follicles without adding any LH so many good responder patients are fine with a pure FSH protocol e.g. only puregon or gonal F, but poor responders may produce a higher number of follicles with a protocol including LH. The difficulty is that there is no concensus on how much LH is needed and how much is excessive. For older ladies or ladies with known egg quality problems, a high amount of LH is probably unhelpful to egg quality.

All these drugs may be supplied as a dry powder which is reconstituted with sterile water for injection, but gonal F is more commonly supplied ready mixed in a prefilled injection pen.

Doctors who support the use of the synthetic drugs usually do so because they believe that they are of higher purity and more consistent concentration and/or allow them to limit the amount of LH - however, since Fostimon was introduced, the amount of LH can be limited whilst still using natural urinary FSH. The synthetic drugs usually come pre-mixed in a pen-type syringe with a dial that allows you to set the dose of drug that you want per injection so some doctors believe that their patients are more likely to inject the correct dose, e.g., of gonal-F, compared to the urinary derived drugs like menopur which are supplied as powders ready for mixing. Mixing drugs sounds difficult, but it is something you quickly get the hang of, but there is always the risk of, say, dropping a needle on the floor (you have to throw it away and get a clean needle), or worse, knocking over an ampoule of mixed solution and wasting an expensive dose.

To prepare drugs like menopur, you use a clean syringe (usually 1ml), and a pink, 18 guage blunt-ended mixing needle (or any other long needle you have available). You snap off the top of an ampoule of dilutant and syringe the dilutent up into the syringe. Then you snap the top off an vial of menopur powder, and inject the dilutent into the vial and swirl it gently to dissolve the powder. Then you syringe up the mixed solution back into the syringe. If you are preparing a dose more than 75 iu, you will then open a second vial of powder, inject the mixed solution into that, swirl, syringe it back up and repeat that step for up to 4 powders (75+75+75+75 = 300 iu). When you have prepared the correct dose, you discard the mixing needle and swap it for (usually) a grey 27 guage half inch injecting needle and then use that to inject the drug into a pinch of belly-flab.

If you are mixing up powders, my advice is to take out the correct number of powders from the box and then put the box away before you start mixing - because its easy to forget how many powders you have already mixed.

Doctors who support the use of urinary FSHs usually do so because they are a) cheaper and/or b) more natural and/or c)contain some LH which seems to help the follicles to grow.

10.3.5 How do I decide whether to have donor egg or own egg IVF?

Those decisions are very emotionally loaded, and in the end, you have to do what feels right to you (and your partner). However, things to bear in mind are:

Even if you have a donor egg baby, your body will have a huge effect on that baby's temperament and health etc before the baby is even born. Although our genes make a big contribution to our baby's temperament and health, what also matters is which genes are switched on and switched off - and the pregnancy (and early childhood) environment makes a big difference to which genes are switched on and switched off. This is called epigenetics. Accordingly, when your baby is born, he will genuinely be the product of the father's sperm, the donor's egg and your uterine environment.

IVF still has a success rate that tends to be less than 50% (the average UK IVF success rate is about 25%). This means that it will usually be more likely than not that, even if you are ultimately successful, it will require more than 1 cycle of IVF, so it may help to look at the cumulative rate of success and the cumulative cost.

Another point to bear in mind is that the risk of miscarriage also increases with the age of eggs, as do the risk of medical conditions for baby e.g., Down's syndrome.

However, bear in mind that eggs are of course not the end of the story. Whilst using excellent eggs can result in good pregnancy rates even with relatively poor sperm, the live birth rate will not be quite as good as if excellent sperm is used as well. In addition, the rates of some medical problems for baby, like autism (and of course, miscarriage rates) increase for older fathers. Although, if you do resort to donor eggs or sperm, you are having to take on trust that the donors do not have undeclared medical issues, because the screening of donors is limited by the honesty of the donors.

In the end, I think if you have to make decisions between donor egg/own egg or donor sperm/own sperm, in the end you still have to do what feels right to you (and your partner), but it is better to understand the risks and economics of the situation up-front and at least bear them in mind.

10.3.6 What strategies are used to improve IVF outcomes?

Problems experienced on a first IVF may provide clues as to what you need to try and optimise for a future cycle. This is not meant to be an exhaustive list but it may give some ideas that you can explore/discuss with your clinic. In general though, in my opinion, it does not make sense to stick with the same protocol for more than 2 or 3 cycles. If it isn't working for you, its time to look at alternatives, and if nothing else, consult with a couple of different clinics to see what approaches they would recommend.

Here is my list of suggested tweaks to investigate/discuss

1) thin lining - see Lining issues (below) and don't forget to check your thyroid (see Thyroid) hormone levels at your GP and make sure you are not borderline or subclinical hypothyroid (for optimal fertility the ideal range for thyroid hormones is a lot narrower than the range that the GP will see as normal for your general health). For donor egg cycles, studies have suggested that if the lining is too old (lining starts to grow shortly after the beginning of your period on a natural cycle or, on from the start of estrogen (or stimms) medication on a down regulated cycle), then implantation rates fall. A significant fall in pregnancy rates has been observed if estrogen medication was started more than 7 weeks before embryo transfer http://jcem.endojournals.org/content/90/7/4399.short2) poor response i.e., less than 4 eggs recovered - 3 months DHEA pretreatment (see supplements), estrogen priming protocols, higher starting doses (often with a step down in dose after a few dys), short protocol with natural cycle start rather than from the pill, long protocol if you have not already tried that, agonist/antagonist conversion protocols - diminished ovarian reserve can also be exacerbated by being subclinically hypothyroid - its definitely worth checking your TSH and FT4 with your GP - see Thyroid. Also, consider treatment with dexamethasone 0.5mg (or equivalent dose of prednisolone) possibly for up to 3 months prior to IVF, in case autoimmune activity (e.g., antiovarian antibodies) are compromising ovarian response. For some ladies with poor response/high AMH there is no advantage in using stimulated IVF and they might actually have a slightly better chance with a natural cycle IVF.3) poor egg quality - resveratrol and/or pycnogenol and/or lycopene pretreatment (also antioxidant diets e.g., those with lots of red/orange/green veg, wheatgrass, spirulina, beetroot powder etc), melatonin, inositol or alpha lipoic acid (mainly for PCOS sufferers), 3 months DHEA pretreatment (but not if there is a high LH:FSH ratio, low SHBG, high testosterone, high antral follicle counts or PCOS), assisted hatching, high protein/low GI diet, limiting LH (by using only/mainly pure FSH until day 4 of stims, and then using a limited dose of LH per day - e.g., using mainly gonal-F, puregon or follistim with either menopur or luveris to add LH) and by using long protocol or a short protocol with a half dose of antagonist which starts on day 1 of stims. Poor egg quality where eggs show thickened zona and none of the eggs recovered are immature can indicate that the stimulation was continued for too long and the eggs are over-mature/atresic (a good indicator of the quality of a batch of eggs is to have 10-40% immature eggs in the batch) - better quality eggs may result from doing a short stimulation and not sacrificing the dominant (and probably best quality) follicles in order to allow the rest of the batch to catch up. Anti-inflammatory diet/supplements if elevated TNFa appears to be involved. Natural cycle IVF or very low dose stimulation protocols are worth considering to maximise egg quality, although this will be at the expense of egg numbers, so you may need to see this as more of a course of, say, 3 natural cycle IVFs before you can decide whether the approach is working for you.4) PCO - as for poor egg quality, but also pill pre-treatment to try to calm the ovaries, low GI diet/healthy BMI, short protocol or agonist/antagonist conversion protocol, assisted hatching, metformin pre-treatment, alpha lipoic acid pretreatment, inositol pretreatment.5) endometriosis/adenomyosis - pycnogenol/resveratrol pre-treatment, prolonged pre-treatment down regulation, natural cycle FET, immune treatment for NKa, anti-inflammatory supplements/diet, letrozole/femara in-cycle treatment.6) slow cleavage embryos - same as poor egg quality7) poor fertilisation rates with IVF - ICSI, possibly assisted hatching, 3 months of antioxidants for the male partner, possibly antibiotics if the male partner is carrying an infection8) OHSS - lower dose of stims, short protocol, alternate days dose of stims (e.g., alternating between 150 iu and 75 iu), 3 months of birth control pill before starting, metformin, low GI diet/healthy BMI, prolonged coasting (i.e., giving fairly low dose stimms e.g., 150 iu and stopping it as soon at least 2 follicles have attained a mean diameter of 18-22mm (on ultrasound) and 50% of the remaining follicles have reached 14-16mm, and waiting (up to 5 days) until the blood estrodial level falls below 2,500pg/ml before giving the HCG trigger shot), cabergoline tablets (a drug which has been shown to reduce the severity of OHSS without damaging egg quality/pregnancy rates), freezing all embryos and having a FET the following month.9) cramping after embryo transfer - see Tocolytics10) implantation problems - clotting (see thrombophilia), infection (see chlamydia, mycoplasma and ureaplasma), natural killer cells (see NK cells), elevated cytokines (see cytokines), lack of blocking antibodies (see LAD), short implantation window (consider starting progesterone at a lower dose then stepping up the dose after a week, and/or switching to a day 3 transfer instead of a blast transfer) - treatments to consider are empirical treatment with clexane and steroids (see Treating empirically), going down the immune testing route and having treatment with steroids/humira/LIT/IVIG/intralipids/clexane and/or newer treatments like PBMC (see PBMC) and neupogen (see G-CSF) or if endometriosis/adenomyosis is suspected 3 months pre-treatment with down reg or in-cycle treatment with femara/letrozole. Also consider hysteroscopy to rule out hard-to-detect scarring in the uterus, to do a mild D&C and maybe a scratch biopsy or fundus cut - and/or a saline wash 2 days before ET.

10.3.7 How can I estimate my chances of IVF working for me?

The suggestions I would make are:be careful that you are looking at the chance of live birth rather than just pregnancy rates, because, depending on age, etc, early losses/miscarriage rates can be quite high and at the end of the day, the live birth rate is much more important than the pregnancy rate. This is particularly important if you are looking at clinics overseas because they tend to only quote pregnancy rates, but you then have to remember that the live birth rate will be quite a lot lower.

donor eggs all ages - 31% live birth rate(but, rates will tend to be slightly higher overseas where there are more young, proven, fertile donors and egg share is rarely used).

Then, think about your personal factors that will mean you are likely to have better or worse odds than the average for your age. You may find the free calculator at ivfpredict.com helpful.

For example, if you have previously had a live birth (without DQa issues), your odds may be double the average for your age group. If you have had more than 3 cycles, then, your basic odds may be significantly lower than the average for your age group. If you have identified and are addressing a significant problem that has likely to have prevented your success in previous cycles, then it may make sense to discount your previous failed cycles. In general, 'unexplained', and mild-moderate male factor issues have better odds of success than uterine problems like endometriosis, or asherman's syndrome. Problems with slow-cleavage, poor response or poor quality eggs/embryos are very hard to gauge until you have done more than 1 cycle unless FSH levels are obviously high because on a first failure, its difficult to know whether it is only a one-off problem due to the wrong dose/duration of stimulation drugs or an indication of permanently poor quality eggs. Problems like clotting issues and NKa are very responsive to treatment and most immune doctors will say that, providing these problems are treated, you will have the same odds as anyone who didn't have these issues - so, if you are using the ivfpredict calculator, personally, I would ignore any previous attempts you have made without treatment. Although, according to Dr Sher, NKa issues caused by a DQa match can be less responsive to immune treatment than other issues.

10.4 IVIG10.4.1 What is IVIG? What does it do?IVIG is a solution of antibodies (proteins – not live cells) extracted from human donor blood, which is purified and pasteurised. It looks like fizzy water and comes in glass bottles. It has been shown to normalise the immune system so is used to up-regulate the immune system in patients who are immunosuppressed (e.g., after cancer treatment), and to down- regulate the immune system in patients with elevated NKa and TNFa, for example. It is thought to work by normalising the signalling mechanism used by the immune system.

10.4.2 How long do the benefits of IVIG last?Studies have shown that it normally lasts for 4-6 weeks.

10.4.3 Who can’t have IVIG?If you have an allergic reaction with IVIG you are not normally not advised to have it in future. Ladies who have very low IgA levels are at high risk of allergic reaction to IVIG and are not normally advised to have it and it is recommended to have your immunoglobulin levels tested (by blood test, possibly at your GP) before having IVIG prescribed.

10.4.4 What are the risks/side effects of IVIG?Some ladies experience no side effects but it is common to feel cold (so take an extra jumper) and a bit headachy (and this may be relieved by taking paracetamol. Dr Gorgy likes you to have eaten and drunk something before the infusion so if you are suffering from morning sickness at the time, you may need to take some biscuits or anything else that you might find easy on your stomach to eat before (and during) your drip (there are shops nearby to the clinic if needed). The main risk is of having a severe and sudden allergic reaction. For this reason, it is only given with a nurse/doctor on hand, at least for the first time. A pre-med of anti-histamine e.g., Piriton/Benadryl is also often given, at least for the initial infusion. As it is a human blood product, although it is purified and the donors are screened (and is produced only in reputable, licensed facilities), it should be free of any communicable diseases, but there is always a small risk that something goes wrong, or that a new virus emerges that is not known and therefore not being tested for.

10.4.5 How is IVIG given?Particularly for your first drip, a premed of either piriton or benadryl is given, or in some clinics an IV dose of piriton. Some clinics also give you additional piriton or benadryl to take afterwards. If you have your drip with a doctor on hand, the premed is sometimes skipped and if you have been fine on previous drips it is often skipped for subsequent drips. The IVIG is given via a cannula in the back of the hand or the crook of the elbow. It is infused slowly over 3-4 hours by IV (so you may want to take a sandwich and a drink with you). If you need to move around during your infusion (e.g., to go the toilet, that isn’t a problem, as you can either take the drip bottle or the whole drip stand with you). The bottles of IVIg usually come in 10g and 5gs, so you will usually need more than one bottle to make up your total dose. The dose given is weight dependent (see below) and also varies between different clinics.

10.4.6 Can I have IVIG administered on a weekend?Dr Gorgy will administer IVIG on a Saturday morning only by special arrangement and only if the appointment is first thing in the morning to ensure the drip is finished by lunchtime. Healthcare at Home will administer it on Saturdays subject to availability and for an extra charge.

10.4.7 Can I have IVIG administered outside of London?Dr Gorgy has a strong preference for you to have your IVIG in his clinic, especially for the first dose, but if this is impractical he may be prepared to write you a prescription for you to arrange for Healthcare at Home to administer. Healthcare at Home (08702400518 – ask for Jade Herrington) can provide nurses nationwide in the UK to administer it (in your home or even at work).

10.4.8 How much does IVIG cost?The dose depends on your body weight (normally its about 400mg/kg but is rounded (usually downwards because of the cost) to the nearest 5g). It normally costs somewhere between £1100 and £1500 per infusion. The current cost prices are (for Octagam brand) net price 2.5 g (50 mL) = £120.00, 5 g (100 mL) = £240.00, 10 g (200 mL) = £480.00 but all pharmacies and clinics will charge a mark-up and a nursing fee on top and the prices may vary significantly depending on supply and demand. In the UK, we normally use either Octagam or Privigen, but Gammagard S/D might be cheaper if you can get hold of it. Octagam and Privigen come ready to use, but Gammagard comes as a powder with a dilutant which needs to be mixed together immediately before use and a special giving kit containing a filter.

10.4.9 How often do I need IVIG?On the Beer protocol followed by Dr Gorgy it is usually started 7-14 days before planned embryo transfer/implantation and given every three-four weeks until either 22 or 31 weeks of pregnancy (occasionally only until 12 weeks if there are only simple immune problems that are well controlled) – although Dr Gorgy will tend to prescribe it at varying intervals depending on your response as shown on NK retests (see Pregnancy). ARGC tend to give it later e.g., around ET. The rationale for extending treatment to 31 weeks is based on a small number of studies which showed that there was some improvement in live birth rate if it was continued until later in pregnancy but after 31 weeks even if there is an immune flare, baby is unlikely to start to be affected until 4-6 weeks later, which is close to due date. In any case, from 31 weeks the amount of ivig antibodies that will cross the placenta is likely to increase so all docs would want to avoid giving it after that just in case this has some unforseen effect.

10.4.10 What supplies do you need?The kit would often include bottles of IVIG, a giving kit and a cannula. The kit may include two small e.g., 50ml, bags of saline for flushing the IV line, antiseptic swabs, latex gloves, sterile drape, adhesive film for sticking the cannula in place, sharps bin and cotton wool balls - or the nurse may have all or some of these. The nurse will usually have a drip stand, thermometer and blood pressure monitor. Some nurses will also use an IV pump to control the flow of the drip automatically, but it can be controlled manually using the standard valve on the giving kit. The nurse will also need to have an anaphylaxis kit containing injections of epinephrine/adrenaline, antihistamines and an oxygen mask. IVIG is normally started at a slow drip rate initially which is then increased e.g. 100ml/hr for 15 minutes, increased to 200ml/hr for remaining infusion if no adverse reaction. For subsequent infusions the faster rate can normally be used from the start. The nurse will need to check your pulse, temperature and blood pressure from time to time during the infusion.

You will also probably want a (hot, sugary) drink and a snack, and possibly a blanket, particularly in cold weather, as it may be difficult to put on a jacket etc when you have the cannula in and start to feel chilly due to the IVIG.

ProtocolDoseage: IVIG 25gPremed: 1 acrivastine tablet to be self-administered by patient 1 hour before IVIG (for subsequent infusions, the premed can be omitted)Route: IV -24g cannula recommended. For first infusion of product, 100ml/hr for 15 minutes, increased to 200ml/hr for remaining infusion if no adverse reaction. For subsequent infusions a rate of 200ml/hr can be used for the whole infusion.Administration: Follow manufacturer's instructions for preparation of product. For Gammagard S/D, prepare at standard 5% protein concentration and use giving kit provided by manufacturer including in-line filter. Record product batch numbers before administration. Observe and assess for adverse drug effects / reactions when collecting and documenting vital sign information.Day of treatment: Administer 7-14 days before embryo transfer. If patient has a positive pregnancy test following treatment, she should have further treatments every 3-4 weeks as prescribed by her doctor. Drug: IVIG. Sterile solution. Store below 25degrees.Contraindications: Selective IgA deficiency. History of anaphylactic episode following previous IVIG infusion. Severe thrombocytopenia o